Wilson & Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry [Eleventh ed.] 9780781734813, 0781734819

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Wilson and Gisvold's Textbook of

ANIC MEDICINAL AND PHARMAC ICAL CHEMIS TRY E

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Wilson and Gisvold's Textbook of

ORGANIC MEDICINAL AND PHARMACEUTICAL CHEMISTRY

ELEVENTH EDITION Edited by

John H. Block, Ph.D., R.Ph. Professor of Medicinal Chemistry Department of Pharmaceutical Sciences College of Pharmacy Oregon State University Corvallis. Oregon

John M. Beale, Jr., Ph.D. Associate Professor of Medicinal Chemistry and Director of Pharmaceutical Sciences St. Louis College of Pharmacy St. Louis, Missouri

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The publisher is not responsible (as a matter of product liability, negligence, or otherwise) For any injury resulting from any material contained herein. This publication contains infonttation relating to general principles ui medical care that should not he construed a.s specific instructions for individual patiettts. Manuthcturers' prnduct information and package inserts should he reviewed lOr current information, including contraindicationt. dosages, and precautions. Prinle'rI in the Uniteg! Stale.s of Anwrieu

First Editton, 1949 Second Edition. 1954 Third Edition. 1956

Filth Edition. 1966 Sixth Edition. 1971 Seventh Edition, 1977

Eighth Edition. 1982 Ninth Edition, 1991 Tenth Edition, 1998

rswrtli Edition, (962

Llbrnry or Congrnas Cataloglng.In.Publkatloit Data Wilson and Gisvold's textbook of organic medicinal and phartnaccutical chemistry.— 11th ed. / edited by John H. Block. John M. Beale Jr. p.

cm,

Includes bibliographical references attd index. ISBN 11-7817-34111-9

I. Pharmaceutical chemistry. 2. Chemistry. Organic. I. Title: Textbook of organic medicinal and pharmaceutical chemistry. II. Wilson. Charles Owens. 1911—2002 10. Gisvold. Ole.

l904- IV. Block. John H. V. Ileak. John Marlowe. IDNLM: I. Chemistry. Pharmaceutical. 2. Chemistry. Organic. QV 744 W754 2ll(9J RS403. 143 2111)4

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2 3 4 5 6 7 8 9 10

l'he Fkrenth Edüion of Wilson and Gisvold's Texibook of Organic and Medicinal Pharmaceutical Charles 0. Wilson q( Jaiine N. !)elgado

Chem i stry is' (kYiica:ed Iv the

Jaime N Delgado 1932—2001

Delgado served as coeditor for the ninth and tenth editions and was continuing

Juime N. this role before his death on October 5, 200 1 . Dr. Dclgado studied with Ole Gisvold, one of the P rofessor in

two founding editors of this textbook, and he was dedicated to maintaining the standards of excellence

established by Gisvold and his coeditor Charles Wilson. He loved teaching medicinal chemistry to students, and this textbook was a powerful aid to him. A graduate of the University of Texas at Austin and the University of Minnesota. Jaime Delgado began his teaching career as an assistant professor at the University of Texas College of Pharmacy in 959. He rose through the academic ranks to become professor and head of the Division of Medicinal Chemistry and a leader in research and graduate education. He essentially built both the graduate program and the Division from scratch, and his publication of research and scholarly works brought national recognition to the department. Although Jaime Delgado became known for his research and scholarship. his first love and his greatest legacy were in teaching and advising undergraduate and graduate students. The University of Texas at Austin awarded him five major teaching awards. and recognized him two times as one of its "best" professors. In 1997. he was elected to the Academy of Distinguished Teachers at the university and was honored as a Distinguished Teaching Professor, a permanent academic title. Former dean James Doluisio described Dr. Delgado's teaching style as "owning the classroom" because of his knowledge. communication skills, and deep conviction that pharmacy is a science-based profession. His enthusiasm and extemporaneous use of the chalkboard were legendary. In addition to his contributions to teaching at the University of Texas, Dr. Delgado traveled extensively in Mexico and South America to present lectures on pharmaceutical education. Jaime Delgado's first contributions 10 the Textbook of Organic Medicinal (111(1 Phannaceutical Chemistry were made as a chapter author in the seventh and eighth editions. Much of the material he presented came from his lecture notes Although he was proud of these contributions, which were expanded in the ninth and tenth editions, he considered his role as coeditor in the latter editions one of the highlights of his distinguished career. Jaime was a true gentleman and a pleasure to have as a collaborator. He will he greatly missed by the editors, authors4 and professional staff for the Textbook. 1

William A. Reiners

Charles 0. Wilson 1911—2002

A

s the chapters for the eleventh edition were being sent to the publisher. I was notified that my

colleague and friend. Charles Wilson. had died shortly Christmas. I-Ic was a product of the Pacific Northwest having received all of his degrees from the University of Washington. His first teaching job was at the now discontinued pharmacy school at George Washington University and then he moved to the University of Minnesota. Charles. along with other medicinal chemistry faculty at the University of Minnesota. saw the need for textbooks that presented modern medicinal chemistry. In 1949. he and Professor Ole Gisvold edited Organic chemistry in Pharmacy, which became the first edition of the Textbook of Medicinal and Pharmaceutical che,nix:rv. Continuing in this tradition. Charles and Professor Tailo Some assumed the authorship of Roger'.c Inorganic Pharmaceutical Chemistry, which included eight editions before its discontinuance. Finally. Charles and Professor Tony Jones started the American Drug Index series. Charles continued his publishing activities after moving to the University of Texas and then assumed the position of Dean of Oregon State University's School ol Pharmacy, where he oversaw a major expansion of its faculty and physical plant. Although a medicinal chemist. Charles devoted considerable time to his chosen pharmacy profession. students, and communily. Charles was an active member of the American Pharmaceutical Association as well as the pharmacy associations in each state where he lived. In addition, he was a registered pharmacist in each state where he taught: Washington. Minnesota, Texas. Oregon, and the District or Columbia. Charles chaired national committees and sections of the American Pharmaceutical Association and the American Association of Colleges of Pharmacy. Related to these, his loyalty to students included organizing student branches of the American Pharmaceutical Association al George Washington University. the University of Minnesota. and the University of Texas. He was actively involved in the local American Red Cross blood program and took the lead in developing the hugely successful student centered blood drives at Oregon State University. In 1960, Charles and his wife, Vaughn. helped launch the AFS (American Field Service) in Corvallis, an international high-school exchange program. He volunteered for Meals on Wheels for over 30 years after his retirement. We certainly miss this fine gentleman and leader of pharmacy education and the pharmacy profession.

John H. Block

PREFACE

For almost six decades, Wilson and Gisvo!d s Textbook of Organic Medicinal and Pharmaceutical chemistry has been a standard in the literature of medicinal chemistry. Generations of students and faculty have depended on this textbook not only for undergraduate courses in medicinal chemistry but also as a supplement for graduate studies. Moreover, students in other health sciences have found certain chapters useful at one time or another. The current editors and authors worked on the eleventh edition with the objective of continuing the tradition of a modem textbook for undergraduate studerns and also for graduate students who need a general review of medicinal chemistry. Because the chapters include

a blend of chemical and pharmacological principles necessary for understanding structure—activity relationships and molecular mechanisms of drug action, the book should be useful in supporting courses in medicinal chemistry and in complementing pharmacology courses.

II is our goal that the eleventh edition follow in the footsteps of the tenth edition and reflect the dynamic changes occurring in medicinal chemistry. Recognizing that the search for new drugs involves both synthesis and screening of large numbers of compounds, there is a new chapter on combinatorial chemistry that includes a discussion on how the process is automated. The power of mainframe computing now is on the medicinal chemist's desk. A new chapter describes techniques of molecular modeling and computational chemistry. With a significant percentage of the general population purchasing altemativc medicines, there is a new chapter on herbal medicines that describes the chemical content of many of these products. The previous edition had new chapters on drug latentiation and prodrugs, immunizing biologicals. diagnostic imaging agents, and biotechnology. Expansion of chapters from the tenth edition includes the antiviral chapter that contains the newest drugs that have changed the way HIV is treated. Dramatic progress in the application of molecular biology to the production of pharmaceutical agents has produced such important molecules as modified human insulins, granulocyte colony-stimulating factors, erythropoietins, and interferons. all products of cloned and, sometimes, modified human genes. The chapter on biotechnology describes these exciting applications. Recent advances in understanding the immune system at the molecular level have led to new agents that suppress or modify the immune response, producing new treatments for autoimmune diseases including rheumatoid arthritis, Crohn's disease, and multiple sclerosis. Techniques of genetic engineering now allow the preparation of pure surface antigens as vaccines while totally eliminating the pathogenic organisms from which they are derived.

The editors welcome the new contributors to the eleventh edition: Doug Henry. Phillip Bowen, Stephen i. Cutler. 1. Kent Walsh, Philip Proteau. and Michael J. Deimling. The editors extend thanks to all of the authors who have cooperated in the preparation of the current edition. Collectively, the authors represent many years of teaching and research experience in medicinal chemistry. Their chapters include summaries of current research trends that lead the reader to the original literature. Documentation and references continue to be an important feature of the book.

We continuc to be indebted to Professors Charles 0. Wilson and Ole Gisvold. the originators of the book and editors of five editions. Professor Robert Doerge. who joined Professors Wilson and Gisvold for the sixth and seventh editions and single-hundedly edited the eighth edition, and Professors

Jaime Dclgado and William Remers who edited the ninth and tenth editions. They and the authors have contributed significantly to the education of countless pharmacists, medicinal chemists, and other pharmaceutical scientists. John H. Block John M. Beale. Jr. 1st

2nd 3rd 4th 5th

1949 1954 1956 1962 1966

Wilson and Gisvold (Organic C'he,,,istrv in Pharmacy) Wilson and Gisvold Wilson Wilson and Gisvold Wilson

6th 7th 8th 9th

1977 1982

10th

1998

1971

1991

Wilson. Gisvold, and Doerge Wilson. Gisvold. and Doerge Doerge Delgado and Remers Delgado and Remers

VI,

*4

A

———1

CONTRIBUTORS

JOHN M. BEALE, JR.,

STEPHEN J. CUTLER,

PH.D.

PH.D.

EUGENE I. ISAACSON, PH.D.

Associate Professor of Medicinal Chemistry and Director of

Professor of Medicinal Chemistry

Professor Emeritus of Medicinal

School of Pharmacy Mercer University Atlanta, Georgia

Chemistry Department of Pharmaceutical

Pharmaceutical Sciences St. Louis College of Pharmacy St. Louis, Missouri

JOHN R.PH.

H. BLOCK, PH.D.,

Professor of Medicinal Chemistry Department ol Pharmaceutical Sciences

College of Pharmacy Oregon State University Corvallis. Oregon .1.

PHILLIP BOWEN, PH.D.

Professor of Chemistry and

Director. Center for Biomolecular Structure and Dynamics Computational Chemistry Building Cedar Street

University of Georgia Athens. Georgia

C.

RANDALL CLARK,

PH.D. Professor of Medicinal Chemistry Department of Pharmacal Sciences School of Pharmacy Auburn University Auburn. Alabama

GEORGE PH.D.

H. COCOLAS,

Professor of Medicinal Chemistry and Dean School of Pharmacy

University of North Carolina at Chapel Hill Chapel Hill. North Carolina

HORACE

G. CUTLER,

PH.D.

MICHAEL J. DEIMLING, R.PH., PH.D. Professor of Pharmacology and Chair Department of Pharmaceutical Sciences

School of Pharmacy Southwestern Oklahoma State University Weatherford, Oklahoma

JACK DERUITER, PH.D.

Atlanta. Georgia

RODNEY L. JOHNSON, PH.D. Professor of Medicinal Chemistry Department of Medicinal Chemistry University of Minnesota Minneapolis. Minnesota

Professor of Medicinal Chemistry

Department of Pharmacal Sciences School of Pharmacy

Auburn University Auburn. Alabama

JACK N. HALL, M.S., R.PH., BCNP Clinical Lecturer Department of Radiology/Nuclear Medicine

College of Medicine. University of Arizona University of Arizona Health Sciences Center Tucson. Arizona

DOUGLAS R. HENRY Advisory Scientist MDL Information Systems. Inc. San Leandro, California

THOMAS J. HOLMES, JR., PH.D. Associate Professor School of Pharmacy Campbell University Buies Creek, North Carolina

Senior Research Professor

Director of the Nutuml Products Discovery Group Southern School of Pharmacy \lcrccr University

Sciences

College of Pharmacy Idaho State University Pocatello. Idaho

TIM B. HUNTER, M.D.

DANIEL A. KOECHEL, PH.D. Professor Emeritus—Pharmacology Department of Pharmacology Medical College of Ohio Toledo. Ohio

GUSTAVO R. ORTEGA,

R.PH., PH.D. Professor of Medicinal Chemistry Department of Pharmaceutical Sciences

School of Pharmacy Southwestern Oklahoma State University Weatherford. Oklahoma

PHILIP J. PROTEAU, PH.D. Associate Professor of Medicinal Chemistry College of Pharmacy Oregon State University Corvallis. Oregon

WILLIAM A. REMERS, PH.D.

Vice-Chairman and Professor

Professor Emeritus

Department of Radiology University of Arizona Tucson. Arizona

Pharmacology and Toxicology University of Arizona Tucson. Arizona

ix

X

Coniri/nuors

GARETH THOMAS, PH.D.

ROBERT E. WILLETTI

Associate Senior I.ecturer The School of Pharmacy and

PH.D.

Auburn University Auburn. Alabama

Biomedical Sciences University of Portsmouth Portsmouth, England

Duo Research. Inc. Denver. Colorado

FORREST T. SMITH, PH.D.

T. KENT WALSH, D.O.

Associate Professor

Director

Department of Pharmacal Sciences School of Pharmacy

Nuclear Medicine Program Southern Arizona V.A. Health Care

Auburn University Auburn. Alabama

Tucson, Arizona

THOMAS N. RILEY, PH.D. Professor of Medicinal Chemistry Department of Pharmacal Sciences School of Pharmacy

System

President

A

s—a —-—4

CONTENTS

vu

Preface

Contributors

CHAPTER 1 Introduction fist,,: H. Block

a,,d Jo/u: ti!. lie::!,'. Jr.

Role of Cytochrome P-450 Monooxygenases in Oxidative Biotransformations Oxidative Reactions Reductive Reactions Hydrolytic Reactions Phase II or Conjugation Reactions Factors Affecting Drug Metabolism

67 69 103 109 111

126

CHAPTER 5 Prodrugs and Drug Latentiation

CHAP I ER 2 Physicochemical Properties Biological Action

in Relation to 3

Joh,: H. Block

Overview Drug Distribution Acid—Base Properties

Statistical Prediction of Pharmacological Activity Combinatorial Chemistry Molecular Modeling (Computer-Aided Drug Design)

Selected Web Pages

3 3

9

C HAPIE R

26

Biotechnology and Drug Discovery

41

142 142 144 152 155

Prodrugs of Functional Groups Bioprecursor Prodrugs Chemical Delivery Systems

17

27

142

/-'orrest T. Smith and C. Randall C/ask History Basic Concepts

6

160

Jo!:,: M. lfrale. Jr.

Biotechnology An Overview Biotechnology and Pharmaceutical Care Literature of Biotechnology Biotechnology and New Drug Development The Biotechnology of Recombinant DNA IrDNA) . Some Types of Cloning Expression of Cloned DNA . Manipulation of DNA Sequence Information New Biological Targets for Drug Development Novel Drug-Screening Strategies Processing of the Recombinant Protein Pharmaceutics of Recombinant DNA (rDNA)Produced Agents Delivery and Pharmacokinetics of Biotechnology .

.

CHAPTER 3 Combinatorial Chemistry

43

Daii,ç'la.c I?. Hrs:rv

.

.

.

.

.

.

.

How It Began: Peptides and Other Linear Structures Drug-Like Molecules Supports and Linkers

Solution-Phase Combinatorial Chemistry Pooling Strategies

Detection, Purification, and Analysis Encoding Combinatorial Libraries High-Throughput Screening (HIS) Virtual (in Silico) Screening Chemical Diversity and Library Design Report Card on Combinatorial Chemistry: Has It Worked' Resources for Combinatorial Chemistry Combinatorial Chemistry Terminology

.

43 46 48 49 50 51

52

53 54 55 58

60 60

Products

Recombinant Drug Products The Interleukins Enzymes Vaccines

Preparation of Antibodies Genomics Antisense Technology Gene Therapy

Afterword

CHAPTER 4 Metabolic Changes of Drugs and Related Organic compounds

173 175 175 182 183 186 187 191

193 194 194

CHAPTER 7 Immunobiologicals 65

Ste-ph:,: J. C':i:ler and Jo!::: H. Block

General Pathways of Drug Metabolism Sites of Drug Biotransformation

.

160 160 160 160 162 166 167 168 169 170 172

65

66

197

Jo/ui M. //eale. Jr.

Cells of the Immune System Immunity Acquisition of Immunity

197

200 206

xi

Xii

Contents

CHAPTER 8

CHAPT

Anti-infective Agents

217

John M. Beak. Jr. Evaluation of the Effectiveness of a Sterilant Alcohols and Related Compounds Phenols and Their Derivatives Oxidizing Agents Halogen-Containing Compounds Cationic Surfactants

.

.

219 219 221

223 223 224 226 228 228 230 247 259 264 268 268 279 279

Dyes

Mercury Compounds (Mercurials) Preservatives

Antifungal Agents Synthetic Antibacterial Agents Antiprotozoal Agents Anthelmintics Antiscabious and Antipedicular Agents Antibacterial Sulfonamides Dihydrofolate Reductase Inhibitors Sulfones

CHAPTER 9 Antimalarials Jo/rn H. Block

Stimulation of Antimalarial Research by War

.

Drug Therapy Cinchona Alkaloids

CHAPTER

283 285

0

Antibacterial Antibiotics

299

Jo/ni M. Beak. Jr.

Historical Background Current Status Commercial Production Spectrum of Activity Mechanisms of Action Chemical Classification Microbial Resistance Antibiotics The Penicillins 13-Lactamase Inhibitors Cephalosporins

Monobactams Aminoglycosides Tetracyclines Macrolides Lincomycins Polypeptides Unclassified Antibiotics

299 299 300 300 300 301 301 301

302 314 318 334 334 341

349 353 355 360

CHAPTER 11 Antiviral Agents

367

R

1

2

390

William A. Remers Tumor Cell Properties Alkylating Agents Antimetabolites Antibiotics Plant Products Miscellaneous Compounds Hormones Signal Transduction Inhibitors Immunotherapy Monoclonal Antibodies Radiotherapeutic Agents Cytoprotective Agents Future Antineoplastic Agents Potential Future Developments

390 394 402 414 424 428 433

438 440 442 444 445 446 448

.

.

CHAPTER 13 Agents for Diagnostic Imaging

454

Tin, Ii. Hunter, T. Kent Walsh, Jack N. Hall Introduction to Radiation Characteristics of Decay Biological Effects of Radiation Radionuclides and Radiopharmaceuticals for Organ Imaging Radionuclide Production Technetium Radiochemistry Fluorine Radiochemistry Gallium Radiochemistry Iodine Radiochemistry Indium Radiochemistry Thallium Radiochemistry Xenon Radiochemistry Radiological Contrast Agents Paramagnetic Compounds Ultrasound Contrast Agents Radiological Procedures

454 456 457

458 461

463 468 468 468 469 472 472 472 475 477 478

C HAPTER 14 Central Nervous System Depressants

485

Eugene I. lsaacson General Anesthetics

485 488 496 503

Anxiolytic. Sedative, and Hypnotic Agents Antipsychotics Anticonvulsant or Antiepiloptic Drugs

CHAPTER 15 central Nervous System Stimulants

510

Eugene I. lsaacson Analeptics

510

Methyixanthines Central Sympathomimetic Agents (Psychomotor Stimulants) Antidepressants Miscellaneous CNS-Acting Drugs

511

512 514 520

CHAPTER 16 Adrenergic Agents

Jo/ru M. Beak, Jr. Classification of Viruses Targets for the Prevention of Viral Infections—Chemoprophylaxis The Infectious Process for a Virus Nucleoside Antimetabolites Newer Agent5 for the Treatment of HIV Infection

E

Antineoplastic Agents

367 367 370 375 382

Rot/tier L Johnson Adrenergic Neurotransmitters Adrenergic Receptors Drugs Affecting Adrenergic Neurotransmission Sympathomimetic Agents Adrenergic Receptor Antagonists

524

.

.

524 527 528 530 539

(tnate,lts

CHAPTER 17

Inhibition of Histamine Release Mast Cell

Cholinergic Drugs and Related

Agents ...

George II. Combs and Stephen J. Cutler Cholinergic Receptors Cholinergic Neurochemistry Cholinergic Agonists Cholinergic Receptor Antagonists Cholinergic Blocking Agents Parasympathetic Postganglionic Blocking Agents Solanaceous Alkaloids and Analogues Synthetic Cholinergic Blocking Agents Ganglionic Blocking Agents Neuromuscular Blocking Agents

.

.

548 548 553 553 558 572 573 574 579 586 589

CHAPTER 18 Diuretics

596

l.)aniel it. At,i'chel

Anatomy and Physiology of the Nephron

596 596

Function

Introduction to the Diuretics Site 1 Diuretics: Carbonic Anhydrase Inhibitors Site 3 Diuretics: Thiazide and Thiazide-Like

601 .

.

Diuretics

Site 2 Diuretics. High-Ceiling or Loop Diuretics Site 4 Diuretics: Potassium-Sparing Diuretics .

.

.

.

.

Miscellaneous Diuretics Emerging Developments in the Use of Diuretics

.

Agents

622 634 642 657 663 668 673 673

Antiarrhyhmic Drugs Antihypertensive Agents Antihyperlipidemic Agents Anticoagulants Synthetic Hypoglycemic Agents Thyroid Hormones Antithyroid Drugs

CHAPTER 20 Local Anesthetic Agents

676

Gureth Thomas Historical Development

676 679 685 687

The Nervous System

Mechanism of Action Administration Factors Influencing the Effectiveness of the Anesthetic Action Rate of Onset and Duration of Anesthesia Secondary Pharmacological Action Structure Action

.

.

.

687 688 689 690

Pain Morphine and Related Compounds Antitussive Agents Anti-inflammatory Analgesics

I)eRuiter

Histamine Histamine Life Cycle Histamine

Antagonists (Antihistaminic Agents)

696 696 700

731

732 752 753

CHAPTER 23 Steroids and Therapeutically Related

Compounds

767

.

.

.

767 768 770

Changes to Modify Pharmacokinetic Properties of Steroids Steroid Hormone Receptors GnRH and Gonadotropins Sex Hormones Chemical Contraceptive Agents Androgens Adrenal Cortex Hormones

770 770 773 775 789 797 803

C H A PT ER 24 Prostaglandins, Leukotrienes, and Other

Eicosanoids Thomnas

818

J. Hohues, Jr.

History of Discovery Eicosanoid Biosynthesis Drug Action Mediated by Eicosanoids COX-2 Inhibitors Design of Eicosanoid Drugs Development of Prostacyclin-Derived Products Eicosanoid Receptors Eicosanoids Approved for Human Clinical Use Prostaglandins for Ophthalmic Use Veterinary Uses of Prostanoids Eicosanoids in Clinical Development for Human Treatment

818 818 822 822 823 823

825 827 828 828 829

CHAPTER 25 Proteins, Enzymes, and Peptide

Hormones Stephen

CHAPTER 21 Histamine and Antihistaminic Agents .... 696

731

Robert E. Willene

Numbering Steroid Biosynthesis Chemical and Physical Properties of Steroids

622

Stephen J. ('iufrr and George H. Cocola.c Antianginal Agents and Vasodilators

717 718 727

CHAPTER 22

605 610 616 618

CHAPTER 19

715

Analgesic Agents

Philip J. Proteau Steroid Nomenclature. Stereochemistry, and

618 619 619

Failure Summary Diuretic Preparations

Stabilizers

Recent Antihistamine Developments: The "DualActing" Antihistamines Histamine H2 Antagonists Histamine H3-Receptor Ligands

603

to Treat Hypertension and Congestive Heart

Tliouius N. Rilm.'v and Jack

XIII

830

J. Cutler and Horace G. Cutler

Protein Hydrolysates Amino Acid Solutions Proteins and Protein-Like Compounds

830 830

Enzymes

835 840 857

Hormones Blood Proteins

Impact of Biotechnology on the Development

831

xiv

Coiue,izs

and Commercial Production of Proteins and Peptides as Pharmaceutical Products Biotechnology-Derived Pharmaceutical Products

CHPTER 28 .

.

858 860

C HAPTER 26 Vitamins and Related Compounds Guslai,, R. Oriega. Michael J. Dei,nling. and Jaime N. !)elgado Lipid-Soluble Vitamins Water-Soluble Vitamins Miscellaneous Considerations

866 867 885 900

CHAPTER 27 An Introduction to the Medicinal

Chemistry of Herbs John M. Beak. Jr. What is an Herb? Herbal Purity and Standardization An Herb Is a Drug Types of Herbs

904 905 905 905 906

Computational Chemistry and ComputerAssisted Drug Design J. Phillip Ilunen Computer Graphics and Molecular Visualization Computational Chemistry Overview

919 .

Force Field Methods Geometry Optimization Conformational Searching Molecular Dynamics Simulations Quantum Mechanics Structure-Based Drug Design arid Pharmacophore Perception Predictive ADME

.

920 922 923 929 930 933 935

939 944

Appendix ('akulated Log P, Log D, and

948

Index

957

CHAPTER 1 Introduction JOHN H. BLOCK AND JOHN M. BEALE, JR.

The discipline of medicinal chemistry is devoted to the discovery and development of new agents for treating diseases.

bacterial drugs with better therapeutic profiles. With the

activity is directed to new natural or synthetic

ment for "nutriceutical," the public increasingly is using so-called nontraditional or alternative medicinals that are

MOSt ol this

organic compounds. Inorganic compounds continue to be important in therapy. e.g.. trace elements in nutritional therapy. antacids, and radiopharmaceuticals. but organic molewith increasingly specific pharmacological activities are clearly dominant. Development of organic compounds has grown beyond traditional synthetic methods. It flow ineludes the exciting new held of biotechnology using the cell'. biochemistry to synthesii.e new compounds. Techniques

ranging l'rom recombinant DNA and site-directed

mutugenesis to fusion of cell lines have greatly broadened the possibilities for new entities that treat disease. The pharmacist now dispenses modified human insulins that provide more convenient dosing schedules, cell-stimulating factors that have changed the dosing regimens for chemotherapy. humaniicd monoclonal antibodies that target specific tissues, and lused receptors that intercept immune cell—generated cytokines.

This hook treats many aspects of organic niedicinals: how they are discovered, how they act, and how they developed into clinical agents. The process of establishing a new pharmaceutical is exceedingly complex and involves the talents ut people from a variety of disciplines. including chemistry.

hiochetnistry. molecular biology, physiology, pharmacology. pharmaceutics, and medicine. Medicinal chemistry, itscif. is concerned mainly with the organic, analytical, and biochemical aspects of this process, hut the chemist must interact productively with those in other disciplines. Thus. medicinal chemistry occupies a strategic position at the interface of chemistry and biology. To provide an understanding of the principles of medicinal

chemistry, it is necessary to consider the physicochemical properties used to develop new pharmacologically active compounds and their mechanisms of action, the drug's mejabolisni including possible biological activities of the metaholites. the importance of stereochemistry in drug design, and the methods used to determine what "space' a drug occupies. All of the principles discussed in this book are based on fundamental organic chemistry. physical chemistry'. and biochemistry.

The earliest drug discoveries were made by random sampling of higher plants. Some of this sampling, although based

on anecdotal evidence, led to the use of such crude plant drugs as opium. belladonna, and ephedrine that have been

important for centuries. With the accidental discovery of penicillin came the screening of microorganisms and the

large number of antibiotics from bacterial and fungal sources. Many of these antibiotics provided the prototypical structure that the medicinal chemist modified to obtain anti-

changes in federal legislation reducing the efficacy require-

sold over the counter, many outside of traditional pharmacy distribution channels. It is important for the pharmacist and

the public to understand the rigor that is required for prescription-only and FDA-approved nonprescription products to be approved relative to the nontraditional products. It also

is important for all people in the health care field and the public to realize that whether these nontraditional products are effective as claimed or not, many of the alternate medicines contain pharmacologically active agents that can potentiate or interfere with physician-prescribed therapy. Hundreds of thousands of new organic chemicals arc prepared annually throughout the world, and many of them are entered into pharmacological screens to determine whether they have useful biological activity. This process of random screening has been considered inefficient, but it has resulted in the identification of new lead compounds whose structures have been optimized to produce clinical agents. Sometimes. a lead develops by careful observation of the pharmacological behavior of an existing drug. The discovery thaL amantadine protects and treats curly influenza A came from a general screen for antiviral agents. The use of amantadine in long-term care facilities showed that it also could he used to treat parkinsonian disorders. More recently. automated high-throughput screening systems utilizing cell culture systems with linked enzyme assays and receptor molecules derived from gene cloning have greatly increased the efficiency of random screening. It is now practical to screen enormous libraries of peptides and nucleic acids obtained from combinatorial chemistry procedures. Rational design, the opposite approach to high-volume screening, is also flourishing. Significant advances in x-ray crystallography and nuclear magnetic resonance have made it possible to obtain detailed representations of enzymes and other drug receptors. The techniques of molecular graphics and computational chemistry have provided novel chemical structures that have led to new drugs with potent medicinal activities. Development of HIV protease inhibitors and an-

giotensin-convcrting enzyme (ACE) inhibitors came from an understanding of the geometry and chemical character of the respective enzyme's active site. Even if the receptor structure is not known in detail, rational approaches based on the physicochemical properties of lead compounds can provide new drugs. For example, the development of cimetidine as an antinuclear drug involved a careful study of the changes in antagonism of H2-histamine receptors induced by varying the physical properties of structures based on 1

2

IViIu,,, and Gi.o'ohlx Textbook of Orga,:ic Medicinal and Pharmaceutical Chen,i.strv

histamine. Statistical methods based on the correlation of physicochcmical properties with biological potency are used

to explain and optimize biological activity. As you proceed through the chapters, think of what prob1cm the medicinal chemist is trying to solve. Why were certain structures selected? What modilications were made to

produce more focused activity or reduce adverse reactiooor produce better pharmaceutical propenics? Was the prototypical molecule discovered from random screcns, or did the medicinal chemist have a structural concept of the or an understanding of the disease process that must be interrupted?

CHAPTER 2 Physicochemical Properties in Relation to Biological Action JOHN H. BLOCK

synthesize a new structure and see what happens—contin— ucs to evolve rapidly as an approach to solving a drug design problem. The combination of increasing power and decreas-

17), suicide inhibitors of monoamine oxidase (see Chapter 14), and the aromatase inhibitors 4-hydroxyandrostenedione and exemestane (see Chapter 23). These pharmacological agents form covalent bonds with the receptor, usually an enxyme's active site. In these cases, the cell must destroy

ing cost of desktop computing has had a major impact on solving drug design problems. While drug design increas-

the receptor or enzynse, or. in the case of the alkylating agents, the cell would be replaced, ideally with a normal

Modem drug design. compared with the classical apa c/lange on an existing compound or proach—k: 's

ingly is bawd on modern computational chemical techniques. it also uses sophisticated knowledge of disease mechanisms and receptor properties. A good understanding

(if how the drug is transported into the body, distributed throughout the body compartments, metabolically altered by

the liver and other organs. and excreted from the patient is required along with the structural characteristics of the receptor. Acid—base chemistry is used to aid in formulation hiodistribution. Structural attributes and substituent patterns w.sponsiblc for optimum pharmacological activity can he predicted by statistical techniques such as regression analysis. Computerized conformational analysis permits the medicinal chemist to predict the drug's three-dimensional shape that is seen by the receptor. With the isolation and structural determination of specific receptors and the availability of computer software that can estimate the three-dimensional shape of the receptor, it is possible to design mole-

cuks that will show an optimum lit to the receptor.

ment calls for the drug's effect to last for a finite period of time. Then, if it is to be repeated, the drug will be administered again, lithe patient does not tolerate the drug well, it is even more important that the agent dissociate from the receptor and be excreted from the body.

DRUG DISTRIBUTION

Oral An examination of the obstacle course (Fig. 2-I) faced by the drug will give a better understanding of what is involved in developing a commercially feasible product. Assume that the drug is administered orally. The drug must go into solution to pass through the gastrointestinal mucosa. Even drugs administered as true solutions may not remain in solution as they enter the acidic stomach and then pass into the alkaline

OVERVIEW

A drug is a chemical molecule. Following introduction into lie body, a drug must pass through many barriers, survive alternate sites of attachment and storage. and avoid significunt metabolic destruction before it reaches the site of action.

usually a receptor on or in a cell (Fig. 2-I). At the receptor. the following equilibrium (Rx. 2-I) usually holds: Drug + Receptor

cell. In other words, the usual use of drugs in medical treat-

Drug-Receptor Complex Pharmacologic Response

(Rx. 2-I) The ideal drug molecule will show favorable binding characienstics to the receptor, and the equilibrium will lie to the right. At the same time, the drug will be expected to dissociate (toni the receptor and reenter the systemic circulation

to he excreted. Major exceptions include the alkylating agents used itt cancer chemotherapy (see Chapter 12). a few inhibitors of the enzyme acetylcholinesterase (see Chapter

intestinal tract. (This is explained further in the discussion on acid—base chemistry.) The ability of the drug to dissolve is governed by several factors, including its chemical structure, variation in particle size and particle surface area, na-

ture of the crystal form, type of tablet coating, and type of tablet matrix. By varying the dosage form and physical characteristics of the drug, it is possible to have a drug dis-

solve quickly or slowly, with the latter being the situation for many of the sustained-action products. An example is orally administered sodium phenytoin. with which variation of both the crystal form and tablet adjuvants can significantly alter the bioavailability of this drug widely used in the treatment of epilepsy. Chemical modification is also used to a limited extent to facilitate a drug reaching its desired target (see Chapter 5). An example is olsalazine, used in the treatment of ulcerative colitis. This drug is a dimcr of the pharmacologically active mesalamine (5-aminosalicylic acid). The latter is not effec-

tive orally because it is metabolized to inactive forms 3

4

Wilson and Gisvolds Textbook of Organic Medicinal and Plwrvnaceuiical Che,ni.urs

Intramuscular or

Subcutaneous Injection

Intravenous Injection

Tissue Depots

DRUG

DRUG

DRUG METAOOLffi

SYSTEMIC CIRCULATION

Serum Albumin

DRUG

DRUG

I

DRUG

DRUG METABOLITES

I

4

I Liver: site of most drug metabolism

1

DRUG METABOLITES

DRUG METABOLITES

I,

bile I

duct

DRUG METABOLITES

j

Intestinal Tract

to,

+

Undesired Etlects

Excretion ot DRUG.DRUG

Feces

Drug must pass through membranes.

Receptors

Kidney

I

METTABOLITES

Drug administered directly Into systemic circulation

Figure 2—1 • Summary of drug distribution.

before reaching the colon. The dimeric form passes through a significant portion of the intestinal tract before being cleaved by the intestinal bacteria to two equivalents of mesalamine. COOH

In contrast, these same digestive enzymes can be usell.

advantage. Chloramphenicol is water soluble enough mg/mL) to come in contact with the taste receptors auth tongue, producing an unpalatable bitterness. To mask ih; intense bitter taste, the palmitic acid moiety is added as ester of chloramphenicol' s primary alcohol. This reduce.' Ihi

0I sal az no

parent drug's water soluhility (1.05 mglmL) enough so iLl it can be formulated as a suspension that passes over bitter taste receptors on the tongue. Once in the inlectjit.. tract, the ester linkage is hydrolyzed by the digestive ases to the active antibiotic chloramphenicol and the set

common dietary fatty acid palmitic acid. NHCCI4C 2 Mesa lwni ne

02N

H—CH-CH2OR

—O—cOH

As illustrated by olsalazine. any compound passing through the gastrointestinal tract will encounter a large number and variety of digestive and bacterial enzymes, which. in theory, can degrade the drug molecule. In practice, a new

drug entity under investigation will likely be dropped from further consideration if it cannot survive in the intestinal tract or its oral bioavailability is low, necessitating parenteral dosage forms only. An exception would be a drug for which

there is no effective alternative or which is more effective than existing products and can be administered by an alternate route, including parenteral, buccal. or transdennal.

R = H Chioramphenicol Palmitate: Olsalazinc

R

and chloramphenicol palntitale are examphi

of prodrugs. Most prodrugs are compounds that are inaLliir

in their native form but are easily metabolized to the agent. Olsalazine and chloramphenicol palmitate are exan pIes of prodrugs that are cleaved to smaller compounds. 0th

of which is the active drug. Others arc metabolic to the active form. An example of this ype of prodru;

Chapter 2 • Physicoehernical Properties iii Rela:io,, to Biological Action

menadionc. a simple naphthoquinone that is converted in lie liver to phytonadione (vitamin

S

passages. The latter, many times, pass into the patient's circulatory system by passive diffusion.

Parenteral Adminisbatlon

Menad lane

Phytonadions (Vitamin 1(2(20)) Occasionally, the prodrug approach is used to enhance the absorption of a drug that is poorly absorbed from the gastrointestinal tract. Enalapril is the ethyl ester of enala. prilic acid, an active inhibitor of angiotensin-converting enzyme (ACE). The ester prodrug is much more readily absorbed orally than the pharmacologically active carboxylic

Many times there will be therapeutic advantages to bypassing the intestinal barrier by using parenteral (injectable) dosage forms. This is common in patients who, because of illness, cannot tolerate or are incapable of accepting drugs orally. Some drugs are so rapidly and completely metabolized to inactive products in the liver (first-pass effect) that oral administration is precluded. But that does not mean that the drug administered by injection is not confronted by obstacles (Fig. 2-I). Intravenous administration places the drug directly into the circulatory system, where it will be rapidly distributed throughout the body. including tissue depots and the liver, where most biotransformations occur (see below), in addition to the receptors. Subcutaneous and intramuscular injections slow distribution of the drug because it must diffuse from the site of injection into systemic circulation. It is possible to inject the drug directly into specific organs or areas of the body. Intraspinal and intracerebral routes will place the drug directly into the spinal fluid or brain, respec-

tively. This bypasses a specialized epithelial tissue, the blood—brain barrier, which protects the brain from exposure

add.

to a large number of metabolites and chemicals. The

CH3

Enalapril: R = C2H5 Enalaprilic Acid: R = H

blood—brain barrier is composed of membranes of tightly joined epithelial cells lining the cerebral capillaries. The net result is that the brain is not exposed to the same variety of compounds that other organs are. Local anesthetics are examples of administration of a drug directly onto the desired nerve. A spinal block is a form of anesthesia performed by injecting a local anesthetic directly into the spinal cord at a specific location to block transmission along specific neurons.

Unless the drag is intended to act locally in the gustrointcstinal tract, it will have to pass through the gastrointestinal mucosal barrier into venous circulation to reach the site of the receptor. The drug's route involves distribution or partihoning between the aqueous environment of the ga.strointes-

tinal tract, the lipid bilayer cell membrane of the mucosal cells. possibly the aqueous interior of the mucosal cells, the lipid bilayer membranes on the venous side of the gastroin(estinal tract, and the aqueous environment of venous circulation. Some very lipid-soluble drugs may follow the route

of dietary lipids by becoming part of the mixed micelles. incorporating into the chylomicrons in the mucosal cells into the lymph ducts, servicing the intestines, and finally entering venous circulation via the thoracic duct. The drug's passage through the mucosal cells can be pa.s-

sive or active. As is discussed below in this chapter. the lipid membranes are very complex with a highly ordered structure. Part of this membrane is a series of channels or tunnels that form, disappear. and reform. There are receptors that move compounds into the cell by a process called pino-

niosis. Drugs that resemble a normal metabolic precursor or intermediate may be actively transported into the cell by the same system that transports the endogenous compound.

On the other hand, most drug molecules are too large to enter the cell by an active transport mechanism through the

Most of the injections a patient will experience in a lifetime will be subcutaneous or intramuscular. These parenteral routes produce a depot in the tissues (Fig. 2-I), from which

the drug must reach the blood or lymph. Once in systemic circulation, the drug will undergo the same distributive phenomena as orally and intravenously administered agents before reaching the target receptor. In general, the same factors

that control the drug's passage through the gastrointestinal mucosa will also determine the rate of movement out of the tissue depot. The prodrug approach described above also can be used

to alter the solubility characteristics, which, in turn, can in. crease the flexibility in formulating dosage forms. The solubility of methyiprednisolone can be altered from essentially water-insoluble methylprednisolone acetate to slightly water-insoluble methylprednisolone to water-soluble mehhylprednisolone sodium succinate. The water-soluble sodium hemisuccinate salt is used in oral, intravenous, and intramus-

cular dosage forms. Methylprednisolone itself is normally found in tablets. The acetate ester is found in topical ointments and sterile aqueous suspensions for intramuscular injection. Both the succinate and acetate esters are hydrolyzed

to the active methylprednisolone by the patient's own systemic hydrolytic enzymes (esterases).

6

Wilson and Gisvold's Textbook of Organi Medicinal and Pharmaceutical Chemi.sirv

Protein Binding Once the drug enters the systemic circulation (Fig. 2-I). it can undergo several events, It may stay in solution, but many

drugs will be bound to the serum proteins, usually albumin tRx. 2-2). Thus a new equilibrium must be considered. Depending on the equilibrium constant, the drug can remain in systemic circulation bound to albumin for a considerable period and riot be available to the sites of the pharmacological receptors, and excretion. Drug + Albumin

Methyiprednisolone: R H Meth)lprednisolone Acetate: R C(=O}CH3 Methyiprednisolone Sodium Succinate: R = C(0)CH2CH2COO' Na'

Another example of how prodrug design can significantly alter biodistribution and biological half-life is illustr,tted by

Drug-Albumin Complex

Protein binding can have a profound effect on the drug's effective soluhility. biodistribution. half-life in the body. and interaction with other drugs. A drug with such poor water solubility that therapeutic concentrations of the unbound (active) drug normally cannot be maintained still can be a very effective agent. The albumin—drug complex acts as a reservoir by providing large enough concentrations of free drug to cause a pharmacological response at the receptor. Protein binding may also limit access to certain body compartments. The placenta is able to block passage of proteins from maternal to fetal circulation. Thus, drugs that normally would be expected to cross the placental harrier and possibly harm the fetus are retained in the maternal circulation, bound to the mother's serum proteins.

two drugs based on the retinoic acid structure used systemically to treat psoriasis. a nonmalignant hyperplasia. Etreti-

nate has a 120-day "terminal" half-life after 6 months of therapy. In contrast, the active metabolite. acitretin. has a 33-

to 96-hour "terminal" half-life. Both drugs are potentially teratogenic. Female patients of childbearing age must sign statements that they are aware of the risks and usually are

Protein binding also can prolong the drug's duration of action. The drug—protein complex is too large to pass

administered a pregnancy test before a prescription is issued.

through the renal glomerular membranes, preventing rapid excretion of the drug. Protein binding limits the amount of

Acitretin, with its shorter half-life, is recommended for a female patient who would like to become pregnant, because it can clear her body within a reasonable time frame. When effective. etretinate can keep a patient clear of psoriasis lesions for several months.

drug available for biotransformation (see below and Chapter 4) and for interaction with specific receptor sites. For example, the large. polar trypanocide suramin remains in the body

0

Etretinate

Esterase CH3CH2OH

0

Acitretin

IRs. 2-2)

Chapter 2

• Phvsicochemical

Properties it, Relation to Riolugical Action

7

Na

Sodium in the protein-bound liwni Iir as long months (11,2 = 51) days). The maintenance dose tbr this drug is based on weekly administration. At first, this might seem to be an advantage to the patient. It can be. but ii also means that, ¼hould the patient have serious adverse reactions, a significam length of tune will be required before the concentration of drug falls below toxic levels. The drug—protein binding phenomenon can lead to some clinically significant drug—drag interactions resulting when one drug displaces another from the binding site on albumin, A large number of drugs can displace the anticoagulant warfarm from its albumin-binding sites. This increases the effective concentration of wurfarin at the receptor, leading to an increased prothrombin time (increased time for clot formatioll) and potential hemorrhage.

Tissue The

Depots

drug can also be stored in tissue depots. Neutral fat

constitutes some 20 to 50% of body weight and constitutes a depot of considerable importance. The more lipophilic the drug, the more likely it will concentrate in these pharmacologically inert depots. The ultra-short-acting, lipophilic barbiturate ihiopental's concentration rapidly decreases below its effective concentration following administration. It "disappears" into tissue protein, redistributes into body fat, and

then slowly diffuses hack out of the tissue depots but in concentrations too low for a pharmacological response.

molecules absorbed from the gastrointestinal tract enter the portal vein and are initially transported to the liver. A signifi-

cant proportion of a drug will partition or be transported into the hepatocyte, where it may be metabolized by hepatic enzymes to inactive chemicals during the initial trip through the liver, by what is known as the first-pass effect (see Chap-

ter4). Lidocaine is a classic example of the significance of the first-pass effect. Over 60% of this local anesthetic antiarrhythmic agent is metabolized during its initial passage through the liver, resulting in it being impractical to administer orally. When used for cardiac arrhythmia.s, it is administered intravenously. This rapid metabolism of lidocaine is used to advantage when stabilizing a patient with cardiac arrhythmias. Should too much lidocaine be administered intravenously, toxic responses will tend to decrease because of rapid biotransformation to inactive metabolites. An understanding of the metabolic labile site on lidocainc led to the development of the primary amine analogue tocainide. In

contrast to lidocaine's half-life of less than 2 hours, tocainide's half-life is approximately IS hours, with 40% of the drug excreted unchanged. The development of orally active antiarrhythmic agents is discussed in more detail in Chapter 19.

CH3

ci'

—

Thus, only the initially administered thiopental is present in high enough concentrations to combine with its receptors. The remaining thiopenlal diffuses out of the tis.sue depots into systemic circulation in concentrations too small to be

C2H5

CH3 Li doca in.

CH3

effective (Fig. 2-I). is metabolized in the liver, and is excreted.

In general. structural changes in the barbiturate series (see Chapter 14) that favor partitioning into the lipid tissue stores decrease duration of action but increase central nervous system (CNS) depression. Conversely, the barbiturates with the slowest onset of action and longest duration of action contain the more polar side chains. This latter group of barbiturates both enters and leaves the CNS more slowly than the more lipophilic thiopental.

Drug Metabolism All substances in the circulatory system, including drugs, inciabolites. and nutrients, will pass through the liver. Most

R

—

,NH3' Ct.

H-C—C) CH3

CH3 Tocoin ide

A study of the metabolic fate of a drug is required for all new drug products. Often it is found that the metabolites are also active. Indeed, sometimes the metabolite is the pharmacologically active molecule. These drug metabolites can pro-

vide leads for additional investigations of potentially new products. Examples of an inactive parent drug that is converted to an active metabolite include the nonsteroidal anti-

8

Wilson and Giscolds Textbook of Organic Medicinal and Pharmaceutical Chemistry

inflammatory agent sulinduc being reduced to the active sultide metabolite: the immunosuppressant azathioprine being cleaved to the purinc antimetabolite 6-mercaptopunne; and purine and pyrimidinc antimetabolites and antiviral agents

being conjugated to their nucleotide form (acyclovir phosphorylated to acyclovir triphosphate). Often both the parent drug and its metabolite are active, which has ted to additional

commercial products, instead of just one being marketed. About 75 to 80% of phenacetin (now withdrawn from the U. S. market) is converted to acetaminophen. In the tricyclic antidepressant series (see Chapter 14). imipramine and ami-

triptyline are N-deniethylated to desipramine and nortriptyline, respectively. All four compounds have been marketed in the United States. Drug metabolism is discussed more fully in Chapter 4.

Although a drug's metabolism can be a source of frustration for the medicinal chemist, pharmacist. and physician and lead to inconvenience and compliance problems with the patient, it is fortunate that the body has the ability to metabolize foreign molecules (xenobiotics). Otherwise. many of these substances could remain in the body for years. This has been the complaint against certain lipophilic chemi-

cal pollutants, including the once very popular insecticide DDT. After entering the body, these chemicals reside in body

tissues, slowly diffusing out of the depots and potentially harming the individual on a chronic basis for several years. They can also reside in tissues of commercial food animals that have been slaughtered before the drug has "washed out" of the body.

The main route of excretion of a drug and its metabolites is through the kidney. For some drugs. enterohepatic circulation (Fig. 2-I). in which the drug reenters the intestinal tract from the liver through the bile duct, can be an important part of the agent's distribution in the body and route of excretion. Either the drug or drug nietabolite can reenter systemic circulation by passing once again through the intestinal mucosa. A portion of either also may be excreted in the feces. Nursing mothers must be concerned because drugs and their metabolites can be excreted in human milk and be ingested by the nursing infant.

CH3CO3H

R = CH3S(O)

Sulinduc:

Active Sulfide Mstibolite:

R • CH3S

One should keep a sense of perspective when learning about drug metabolism. As explained in Chapter 4. drug

Azathtoprine

6-Marcaptopur

metabolism can be conceptualized as occurring in two stages or phases. Intermediate metabolites that are pharmacologically active usually are produced by phase I reactions. The products from the phase I chemistry are converted into inactive, usually water-soluble end products by phase II reac-

toe

(ions. The latter, commonly called conjugation reactions. can be thought of as synthetic reactions that involve addition

of water-soluble substiiucnts. In human drug metabolism. the main conjugation reactions add glucuronic acid, sulfate. or glutathione. Obviously, drugs that are bound to serum protein or show favorable partitioning into (issue depots are going to be metabolized and excreted more slowly for the H

reasons discussed above. This does not mean that drugs that remain in the body for longer periods of time can be administered in lower doses or be taken fewer times per day by the patient. Several variables determine dosing regimens, of which the affinity of the drug for the receptor is crucial. Reexamine Reaction 2-I and Fig-

R

ure 2-I. If the equilibrium does not favor formation of the drug—receptor complex, higher and usually more frequent doses must be administered. Further, if partitioning into tissue stores or metabolic degradation and/or excretion is favored, it will take more of the drug and usually more frequent administration to maintain therapeutic concentrations at the

R

R R =

01-i

cico

receptor.

Receptor pH3

CHCH2CH2N5 R

a

Aintiriptyilne:

R

Nortrlptyiln.:

R — H

Cit3

Imipramln.: Desipremine:

R • Cit3 R • H

With the possible exception of general anesthetics (see Chapter 14). the working model for a pharmacological response consists of a drug binding to a specific receptor. Many drug receptors are the same as those used by endoge-

nously produced ligands. Cholincrgic agents interact with

Chapter 2 • the same receptors as the neurotransrnitter acetylcholine. Synthetic corticosteroids bind to the same receptors as corti-

sone and hydrocortisone. Often, receptors for the same Iigand are found in a variety of tissues throughout the body. The nonsteroidal anti-inflammatory agents (see Chapter 22) inhibit the prostaglandin-fomiing enzyme cyclooxygenuse. which is found in nearly every tissue. This class of drugs has a long list of side effects with many patient complaints. Note in Figure 2-I that, depending on which receptors contain bound drug. there may be desired or undesired effects. This is because a variety of receptors with similar structural requirements are found in several organs and tissues. Thus. the nonsteroidal anti-inflammatory drugs combine with the desired cyclooxygenase receptors at the site of the inflamma-

tion and the undesired cyclooxygenase receptors in the gastroiinestinal mucosa. causing severe discomfort and sometimes ulceration. One of the "second-generation" is claimed to cause less sedation because it does not readily penetrate the blood—brain untihistamines.

barrier. The rationale is that less of this antihistamine is available for the receptors in the CNS. which are responsible for the sedation response eharactenstic of anlihistamines. In contrast, some antihistamines are used for their CNS depres. sam activity because a significant proportion of the adminis-

tered dose is crossing the blood—brain barrier relative to binding to the histamine H1 receptors in the periphery. Although ii is normal to think of side effects as undesirable, they sometimes can he beneficial and lead to new prod-

ucts. The successful development of oral hypoglycemic agents used in the treatment of diabetes began when it was found that certain sulfonamides had a hypoglycemic effect. Nevertheless, a real problem in drug therapy is patient compliance in taking the drug as directed. Drugs that cause serious problems and discomfort tend to be avoided by patients.

Swnmary One of the goals is to design drugs that will interact with receptors at specific tissues. There are several ways to do this, including (a) altering the molecule, which, in turn, can change the hiodistribution; (b) searching for structures that show increased specificity for the target receptor that will produce the desired pharmacological response while decreasing the affinity for undesired receptors that produce adverse responses: and (c) the still experimental approach of attaching the drug to a monoclonal antibody (see Chapter 7) that will bind to a specific tissue antigenic for the antibody. Biodistribulion can be altered by changing the drug's solubility. enhancing its ability to resist being metabolized

usually in the liver), altering the fortnulation or physical characteristics of the drug, and changing the route of administration. If a drug molecule can be designed so that its binding to the desired receptor is enhanced relative to the undesired receptor and biodistribution remains favorable, smaller doses of the drug can be administered. This, in turn, reduces the amount of drug available for binding to those receptors responsible for its adverse effects.

The medicinal chemist is confronted with several challenges in designing a bioactive molecule. A good fit to a specific receptor is desirable, but the drug would normally be expected to dissociate from the receptor eventually. The specificity for the receptor would minimize side effects. The drug would be expected to clear the body within a reasonable

Propertie.s in Relation to Biological Action

9

time. Its rate of metabolic degradation should allow reasonable dosing schedules and, ideally, oral administration. Many times, the drug chosen for commercial sales has been selected from hundreds of compounds that have been screened. It usually is a compromise product that meets a medical need while demonstrating good patient acceptance.

ACID—BASE PROPERTIES Most drugs used today can be classified as acids or bases. As is noted shortly. a large number of drugs can behave as

either acids or bases as they begin their journey into the patient in different dosage forms and end up in systemic circulation. A drug's acid—base properties can greatly iniluence its biodistribution and partitioning characteristics. Over the years. at least four major definitions of acids and bases have been developed. The model commonly used in pharmacy and biochemistry was developed independently by Lowry and Brønsted. In their definition, an acid is defined as a proton donor and a base is defined as a proton acceptor. Notice that for a base, there is no mention of the hydroxide ion.

Acid-Conjugate Base Representative examples of pharmaceutically important acidic drugs are listed in Table 2-1. Each acid, or proton donor, yields a conjugate base. The latter is the product after the proton is lost from the acid. Conjugate bases range from the chloride ion (reaction a), which does not accept a proton

in aqueous media, to cphedrine (reaction h), which is an excellent proton acceptor. Notice the diversity in structure of these proton donors. They include the classical hydrochloric acid (reaction a). the weakly acidic dihydrogen phosphate anion (reaction b), the ammonium cation as is found in ammonium chloride (reac-

tion c), the carboxylic acetic acid (reaction d). the enolic form of phenobarbital (reaction e), the carboxylic acid moiety of indomethacin (reaction J), the imide of saccharin (reaction g), and the protonated amine of ephedrine (reaction It). Because all are proton donors, they must be treated as acids when calculating the pH of a solution or percent ionization of the drug. At the same time, as noted below, there are important differences in the pharmaceutical properties of ephedrine hydrochloride (an acid salt of an amine) and those of indomethacin. phenobarbital. or saccharin.

Base-Conjugate Add The Brønsted-Lowry theory defines a base as a molecule that accepts a proton. The product resulting from the addition of a proton to the base is the c'onjugate acid. Pharmaceutically important bases are listed in Table 2-2. Again, there are a variety of structures, including the easily recognizable base sodium hydroxide (reaction a): the basic component of an important physiological buffer, sodium monohydrogen phosphate (reaction b), which is also the conjugate base of dihydrogen phosphate (reaction b in Table 2-I); ammonia (reaction c), which is also the conjugate base of the ammonium cation (reaction c in Table 2-I); sodium acetate (reaction d), which is also the conjugate base of acetic acid (reac-

tion d in Table 2-I); the enolate form of phenobarbital

10

Wilson and Gisvold's Textbook of Organic Med

TABLE 2—1

Examples of Adds

—.

Acid (a)

Hy&ochlonc acid

H•

—.

MCI

+ 4

Conjugate Base

Cl-I

phosphate (monobasic sodium phosphate)

0)

Sodium

(c)

Aninonium chlondn NH4CI (NH44. CIiI

(d)

Acetic acid CH3COOH Phenobarbitat

(e)

an,J Pharmaceutical Chemicu-v

—H

+

—.

+

H4

—H

+

— H'

+

NaHPO02

N

NH

(I)

tndon,ethacin

0

O

// C

\OH

— H4

(9)

+

Saccharin

"p

// +

00 (hi

Ephedrine hydrochiotide ,CH3

CR3

(Clia

—.

+

The Midiwu muon and chlonde anion do not mike paul In

(reaction e), which is also the conjugate base of phenobarbital (reaction e in Table 2-I the carboxylate form of indo-

in Table 2.1 are the reactant bases in Table 2-2. Also, notice that whereas phenobarbital, indomethacin, and saccharin are

methacin (reaction ft. which is also the conjugate base of indomethacin (reaction fin Table 2-I); the imidate form of saccharin (reaction g). which is also the conjugate base of

un-ionized in the protonated form, the protonated (acidic)

saccharin (reaction g in Table 2-I); and the amine ephedrine (reaction I,), which is also the conjugate base of ephedrine hydrochloride (reaction h in Table 2-I). Notice that the con-

forms of ammonia and ephedrine are ionized salts (Table 2I ). The opposite is true for the basic (proton acceptors) forms of these drugs. The basic forms of phenobarbital. indomethacm, and saccharin are anions, whereas ammonia and ephedrine are electronically neutral (Table 2-2). Remember that

jugate acid products in Table 2-2 are the reactant acids in Table 2-I. Conversely, most of the conjugate base products

each of the chemical examples in Tables 2-I and 2-2 can function as either a proton donor (acid) or proton acceptor

Chapter 2 • Phv,ci,-oclu',,,ical Properties in Relation a, Biological Action

Examples of Bases

TABLE 2—2

Base (a)

WaOH (Na". 0H1 Sodium monohydrogen

Ic)

Ammonia

tel

H'

+

H' —

acetate

CH3COONa Phenobarbial sodium H..C

Conjugate Add H.,0

+

Na"

+

2Na"

(dibasic sodium phosphate)

(2Na'",HP04

Sodium

—.

+

Sodium hydroxide

(Or

dl

11

I

Na")

+

Ii'

+

H'

+

H' — CI-(3COOH

+

Na"

+

H'

+

Na'"

+

Na'"

+

Na"'

—.

NH4

0 N

)—O (Na')" NI-i

(I)

Indocnelhaciri sodium

0

0

I,

I, C

/

"

C

0(Na)" +

H'

0 (gt

\=!

Saccharin sodium

0

0

//

Ii

C

(Na)"

+

0EJH 00

H'

S.

//\\

00 (hi

\OH

Ephedrine CH3

cl-i.'

/

+

H'

—

H2N I'

OH The sontinin caIu,,n is preseni only to mainhui,i

b.iInncc-. S plays no direel acid -base title.

(base). This can best be understood by emphasizing the conof conjugate acid—conjugate base pairing. Complicated as ii may seem at lit-st. conjugate acids and conjugate bases are nothing more than the products of an acid—base reaction.

In other words, they appear to the right of the reaction arrows. Examples from Tables 2-I and 2-2 are rewritten in Table 2-3 as complete acid—base reactions. careful study of Table 2-3 shows water functioning as a proton acceptor (base) in reactions a. c-. e. g. i. k. and in and a proton donor (base) in reactions I,, d.f 11.1, I. and a, Hence.

water is known as an ti,nphotes-,e substance. Water can be either a weak base accepting a proton to form the strongly acidic hydrated proton or hydroniuni ion 1-1.10 (reactions a. c. x'. i, k. and in). or a weak acid donating a proton to form the strongly basic (proton accepting) hydroxide anion OH- (reactions b, d. I.,), I. and a).

Acid Strength While any acid—base reaction can be wrttten as an equilib-

rium reaction, an attempt has been made in Table 2-3 to

12

Wilson and Gixr'old.c 7'exthook

of Organic Medici,uzl and Pharmaccuth'al C'he,nis:rr

the Exception of Hydrochloric Acid, Whose Conjugate Base (C1) Has No Basic Properties in Water. and Sodium Hydroxide. Which Generates Hydroxide, the Reaction of the Conjugate Base in Water is Shown for Each Acid) TABLE 2—3 Examples of Acid—Base Reactions (With

Add

+

Base

Hydrochlonc acid (a)

HCI

Conjugate Acid

+

Conjugate Base

+

H2O

— H30

+

Cl -

+

NaOH

—.

Sodium hydroxide

H20

=

+

OH -(Na

Sodium dihydrogen phosphate and its conjugate base, sodium monotiydrogen phosphate + H30 H30' (c) H2pO4.(Na)a + HPO42_(2Naja (ci) H20

+

HP042 - (Na

+

OH1N8)a

Asnmonlum chloride and Its conjugate base. ammonIa + H20 (o) + NH1 H20 (9

+

NH3

+

OH -

+

CH3COO

+

OH1Na')'

(b)

=

H30'(cI-r

Acetic acid and Its conjugate base, sodium acetate + H20 (g) CH3COOH (h)

+

H3O

H30

CH3COO1NaIa

_ CH3COOH

Indornelhacan and its conjugate base. Indomethacin sodium, show the Identical acid—base chemistry as aceticactd and sodium acetate, respectively. Pttenobarbatal and its conjugate base. phenobarbital sodium

CH30

CH10

+

H30

H20

H3C

Ii)

+

o

+

H30

+

OHiNar

Saccharin and its conjugate base, saccharin sodium

0

'7 +

On)

+

00 0

,,0

// (I)

(Nala

+

00

+

cPo

Ephedrlne HCI and itS conjugate base, ephedrnse CH3

CH3

/

(Cue +

(m)

H2O

+ ,,Cl-13

1CH3

HN (',)

The

H20

+

OH1NaI°

CH3

anion and ..odinni canon are parsern aillili to autainlain charge balance. Thc,.c anions piay no other acid—baserole.

+

Chapter 2 • Phvsicothe,nical !'ropcr,ies in Relation to Biological Action tndicatc which sequences are unidirectional or show only a small reversal. For hydrochloric acid, the conjugate base. Cl. is such a weak base that it essentially does not function as a proton acceptor. That is why the chloride anion was not included as a base in Table 2-2. In a similar manner, water is such a weak conjugate acid that there is little reverse reaction involving water donating a proton to the hydroxide anion of sodium hydroxide.

Two logical questions to ask at this point are how one in which direction an acid—base reaction lies and to what extent the reaction goes to completion. The common physical chemical measurement that contains this information is known as the pK,. The pK, is the negative logarithm of the modified equilibrium constant. K,. for an acid—base reaction written so that water is the base or proton acceptor. It can he derived u.s follows: Assunie that a sveak acid. HA. reacts with water. Acid

Conj.

Conj. Acid

Base

HA + U.O = H,0

Base

+

IRs. 23)

A

The equilibrium constant. K01. for Reaction 2-3 is K

1H50 llA

—

ucidl[conj. hasel lacidlihasel

—

I

—

—

Equation 2-7 ix more commonly called the HendersonHasselbalch equation and is the basis for most calculations involving weak acids and bases. It is used to calculate the pH of solutions of weak acids, weak bases, and buffers consisting of weak acids and their conjugate bases or weak bases

and their conjugate acids. Because the pK, is a modified equilibrium constant, it corrects for the fact that weak acids do not completely react with water. A very similar set of equations is obtained from the reaction of a protonated amine. BH . in water. The reaction is Conj.

Acid

Conj.

Acid

Base

BH' + H20

+

Base B

Wcightl1()

H101 =

MW110

—

—

—

18 g

K

—

— —

Iconi. acid llconi. bawl lacidlibasel

= K01(55.5) =

IH5OIIBI

= lconj. acidllconj. basel

lacidi (Eq. 2-9)

2-10).

pH = pK, + tog

181

pK, + log

Icrnii. basel

Thu.'.. with [H201 = 55.5, Equation 2-I can be simplified

(Eq. 2-10)

(Eq. 2-2)

pH = pK, + log

By definition. pK., = —log K,

(Eq. 2-3)

and

pH = —log

(Eq. 2-4)

The modified equilibrium constant. K,. is customarily converted to pK, (the negative logarithm) to use on the same scale as pH. Therefore, rewriting Equation 2-2 in logarithmic fonn produces

Substituting Equations 2-3 and 2-4 into Equation 2-6 produces

log

1Al

pK, + log

lconi. base]

lacidl

lacidi

(Eq. 2-lI)

What about weak bases such as amnines? In aqueous solu-

tions. water functions as the proton donor or acid (Rx. 2-5). producing the familiar hydroxide anion (conjugate base). Base Acid 1-1.0 + B

Rearranging Equation 2-5 gives

—log 1110' I = —log K,, + log lA1 — log (HAl (Eq. 2-6) = —log K, + log lconj. hasel — log laeidl

lconj. base]

With this version of the equation, there is no need to remember whether the species in the numerator/denominator is ionized (A/HA) or un-ionized (B/BH The molar concentration of the proton acceptor is the term in the numerator. and the molar concentration of the proton donor is the denominator term.

log K, = log IH,0'l + log IA1 — log IHAI (Eq. 2-5) = log H,0 I + log lconj. busel — log lacidl

p11 = pK,

lacidl

Rather than trying to remember the specific form of the Henderson-Hasselbalch equation for an HA or BH acid, it is simpler to use the general form of the equation (Eq. 2II) expressed in both Equations 2-7 and 2-10.

=

lucidl

8

Rearranging Equation 2-9 into logarithmic form and substituting the relationships expressed in Equations 2-3 and 2-4 yields the same Henderson-Hasselbalch equation (Eq.

55.5 M

= Iconi. acid Jlconj. bascl

(Eq.

Notice that Equation 2-8 is identical to Equation 2-I when the general [conj. acid Jlconj. base] representation is used. Therefore, using the same simplifying assumption that svater remains at a constant concentration of 55.5 M in dilute solutions. Equation 2-8 can be rewritten as

—

to

(Rx. 2-4)

The equilibrium constant.

(Eq. 2.1)

In a dilute solution of a weak acid, the molar concentration of water can be treated as a constant, 55.5 M. This number is based on the density of water equaling I. Therefore. I L of water weighs 1000g. With a molecular weight of 18, the molar concentration of water in I L of water is

13

Conj. Acid BH

Conj. Base

+ 0H

(Rx. 2-5)

Originally, a modified equilibrium constant, the pK5, was derived following the same steps that produced Equation 22. it is now more common to express the basicity of a chemical in terms of the pK,. using the relationship in Equation 2-12.

(Eq. 2-7)

pK,, = pKh — 14

(Eq. 2-121

14

'leribiiok of' ()rganir Medit'inal giiid P/,ar,naeeiuical ClwnrLs:rt

Wilson and

TABLE 2—4 Examples of Calculations Requiring the 1

in the

What Is the ratio of eptiedulne to ephedrune l'lCt Intestinal tract at pH 8.0? Lisa Equation 2-11.

80—9.6+tog

[ephedrune) —1.6

[pheliHOl

0025

The number whose tog is —1.6 Ia 0025, meaning that there are

25 parts ephedrine for every 1000 pails ephedrine Nd in the intestinal tract whose environment is pH 8.0. 2 What Is the pH ota buffer containing 0.t M acetic acid (p1C—R

R4N'—°l

—OH--0=

1-7

\/ —OH--fl /\

NR3

b8 vanderWaals

0.5-1

ally exists. Thermodynamic arguments on the gain in en-

surface of the receptor have been proposed to validate a hydrophobic bonding nmdel. There are two problems with this concept. First, the term /zvdrop/wbk implies repulsion. The term for attraction is hsdrophiliciiv. Second. and perhaps more important. there is no truly water-free region on

1-7

0C

the concept of hydrophobic bonds has developed. There has been considerable controversy over whether the bond actu-

tropy (decrease in ordered state) when hydrophobic groups cause a partial collapse of the ordered waler structure on the

C

1-7

valine. isolcucine. and leucine" arc commonly used to explain why a nonpolar substituent at a particular position on the drug molecule is important for activity. Over the years.

\l/CC\1/

the receptor. This is true even in the areas populated by the nonpolar amino acid side chains. An alternate approach is to consider only the concept of hydrophilicity and lipophilicity. The predominating water molecules solvate polar moieties,

effectively squeezing the nonpolar residues toward each other.

1

1,0.5 .. l.rI'lo fl

See text

AIi'cfl. A Sololiso Toso.il>. Now York. loho Wik) &

956; 181.

as would thc corresponding groups on a biological receptor. Relatively little net change in tree energy would be expectcd in exchanging a hydrogen bond with a water molecule for one between drug and receptor. However, in a drug—receptor combination, several forces could be involved, including the

hydrogen bond, which would contribute to the stability of the interaction. Where multiple hydrogen bonds may be formed, the total effect may be sizable, such as that demon-

strated by the stability of the protein o helix and by the stabilizing influence of hydrogen bonds between specific base pairs in the douhle.helical structure of' DNA. Van der WooLs forces are attractive forces created by the polanzahility of molecules and are exerted when any two uncharged atoms approach each other very closely. Their

Steric Feateres of Drugs Regardless of the ultimate mechanism by which the drug and the receptor interact, the drug must approach the receptor

and fit closely to its surface. Steric factors determined by the stereochemistry of the receptor site surface and that of the drug molecules are, therefore, of primary importance in determining the nature and the efficiency of the drug—recep-

tor interaction. With the possible exception of the general anesthetics, such drugs must possess a high structural speci-

ficity to initiate a response at a particular receptor. Some structural features contribute a high structural rigidity to the molecule. For example. aromatic rings are planar. and the atoms attached directly to these rings are held in the plane of the aromatic ring. Hence, the quaternary nitrogen and carbamate oxygen attached directly to the benzene ring in the cholinesterase inhibitor neostigminc are restricted to the plane of the ring, and consequently, the spatial arrangement of at least these atoms is established.

is inversely proportional to the seventh power of the distance. Although individually weak, the summation of their forces provides a significant bonding factor in highermolecular-weight compounds. For example. ii is not possible to distill normal alkanes with more than 8() carbon atonls. because the energy of —80 kcal/mol required to separate the molecules is approximately equal to the energy required to break a carbon—carbon covalent bond. Rat structures, such as aromatic rings. pennut close approach of atoms. With van ikr Wuals' forces of —0.5 to I .() kcal/mol for each atom. about six carbons (a benzene ring) would he necessary to match the strength of a hydrogen bond. The aromatic ring

c, p—o H3C'—N CR3

N•est igm!nø

The relative positions of atoms attached directly to multiand tran,s ple bonds are also Fixed. For the double bond.

isomers result. For example. diethylslilbestrol exists in two fixed stercoisomeric forms: irans-diethylstilbestrol is estro-

32

tt'ilsøn and

Textbook of Organic Medicinal and Pharmaceutical Chemistry

genic. whereas the cix isomer is only 7% as active. In trailsdiethyistilbestrol. resonance interactions and minimal steric interference tend to hold the two aromatic rings and connecting ethylene carbon atoms in the same plane.

for interacting with a biological receptor in a structurally specilic manner. The United Stales Pharmacopeia recognizes that there are drugs with vinyl groups whose commercial form contains both their E and Z isomers. Figure 2-14 provides four examples of these mixtures. More subtle differences exist for conformasional isomers,

Like geometric isomers, these exist as different arrangements in space for the atoms or groups in a single classic structure. Rotation about bonds allows interconversion of conformational isomers. However, an energy barrier between isomers is often high enough for their independent

trens.Dl.SliySslI lb.strol

H5C2

existence and reaction. Differences in reactivity of functional groups or interaction with biological receptors may be due to differences in steric requirements of the receptors. In certain semirigid ring isomers show significant differences in biological activities. Methods for calculating these energy harriers are discussed in Chapter 28.

Open chains of atoms. which form an important part of many dnig molecules, are not equally free to assume all possible conformations; sonic are sterically preferred. Energy barriers to free rotation of the chains are present, be-

C2H5

cls-Di.thylstllb.strol Geometric ,so,,wrs, such as the cix and the lran.s isomers, hold structural features at different relative positions in space. These isomers also have signiticantly different physical and chemical properties. Therefore, their distributions in the biological medium are different, as arc their capabilities

cause of interactions of nonbonded atoms. For exumple. the atoms tend to position themselves in space so that they occupy staggered positions, with no two atoms directly facing each other(eclipsed). Nonhonded interactions in polymethyIene chains tend to favor the most cxtendcd anti conformations, although sonic of the partially extended gauche conformations also exist. Intramolecular bonding between

C2H5

_,CH2 C2H5

Z-Clomlphene

Z-Doxepln: R1 E-Doxepln: R, H: R2 •

CH2

E-Clomiphene

R2 • H

Z-Cefprozil: R, E-Cefprozll: R1

H; R2 = Gil3

Figure 2—14 • Examples of E arid Z isomers,

R2

H

Chapter 2 •

/

;cçi

H

H

CH3

n.bulane anti conformation

/

ides, a planar configuration is favored in which minimal

H

steric interference of bulky substituents occurs. Hence, an ester may exist mainly in the anti, rather than the gauche. form. For the same reason, the amide linkage is essentially planar, with the more bulky substituents occupying the anti

3-amlno-n-propanol eclipsed conformatIon

0

0

"0 resonance stabilized

anti

gauche

Stabilized planar structure of esters

0 II ,_152

N'

/

R2

H

H

anti

33

substituent groups can make what might first appear to be an unfavorable conformation favorable. The introduction of atoms other than carbon into a chain strongly influences the conformation of the chain (Fig. 215). Because of resonance contributions of forms in which a double bond occupies the central bonds of esters and am-

H H3Q

H

Properties in Relation to !luilogwal Action

resonance stabilized

gauche

position. Therefore, ester and amide linkages in a chain tend to hold bulky groups in a plane and to separate them as far as possible. As components of the side chains of drugs. ester and amide groups favor fully extended chains and also add polar character to that segment of the chain. In some cases, dipole—dipole inleracflons appear to influence structure in solution. Methadone may exist partially in a cyclic fonn in solution because of dipolar attractive tbrces between the basic nitrogen and carbonyl group or because of hydrogen bonding between the hydrogen on the nitrogen and the carbonyl oxygen (Fig. 2-16). In either conformation. methadone may resemble the conformationally more rigid potent analgesics including morphine. meperidine. and their

analogues (see Chapter 23). and it may be this form that interacts with the analgesic receptor. Once the interaction between the drug and its receptor begins, a flexible drug molecule may assume a different conformation than that pre-

Stabilized planar structure of amides

Figure 2—15 • Effect of noncarbon atoms on a molecule's configuration

dicied from solution chemistry. An intramolecular hydrogen bond, usually formed between donor hydroxy and amino groups and acceptor oxygen and nitrogen atoms, might he expected to add stability to a

particular conformation of a drug in solution. However, in aqueous solution, donor and acceptor groups tend to be

Methadone CU3

CU,

j

— H,

2''

08 'H

/\H,

I

4 5NH ""CH,

H3c

Figure 2—16 • Stabilization of conformations by secondary bonding forces.

Methadone stabilized by hydrogen bonding

Methadone stabilized by dlpolar interaclions

34

and Gi,crohl'.c Texthaok of Organic Mrdicinal and Phurniaceuticu! ('hesnlsUv

bonded to water, and little gain in free energy would be achieved by the formation of an intramolecular hydrogen bond, particularly if unfavorable steric fuctors involving nonbonded interactions were introduced in the process. Therefore, internal hydrogen bonds likely play only a secondary role to steric factors in determining the conformutional distribution of flexible drug molecules.

R1

H

effects (Fig. 2-17). (+ )-trans-2-Acetoxycyclopropyl it)methylammoniurn iodide, in which the quaternary nitrogen

Hydrogon.bonding donor groups

0=0: R3

Hydrogen-bonding acceptor groups

Conformatlonal Flexibility and Multiple Modes of Action It has been proposed that the conlormational flexibility of most open-chain neurohormones. such as acetylcholine. epi-

nephrine. scrotonin. histamine, and related physiologically active biomolecuics. permits multiple biological effects to be produced by each molecule, by virtue of their ability to.

0

OH3

interact in a different and unique conformation with different biological receptors. Thus, it has been suggested that acetylcholine may interact with the muscarinic receptor of postganglionic parasympathetic nerves and with acetylcholinesterase in the fully extended conformation and, in a different, more Iblded structure, with the nicotinic receptors at ganglia and at neuromuscular junctions (Fig. 2-17). Conformationally rigid acetylcholine-like molecules have been used to study the relationships between these various possible conformations of acetylcholine and their biological

atom and aectoxyl groups are held apart in a conformation approximating that of the extended conformation of acetylcholine, was about 5 times more active than acetylcholine in iLs muscarinic effect on dog blood pressure and was as active as acetylcholine in its muscarinic effect on the guinea pig The (+ I-trans isomer was hydrolyzed by acetylcholincsterase at a rate equal to the rate of hydrolysis of acetylcholine. It was inactive as a nicotinic agonist. In COfltrust, the (—)-tran.s isomer and the mixed ( ± )—cis isomers were, respectively. 1/500 and 1/10.00() as active as acetylcholine in muscarinic tests on guinea pig ileum and were

inactive as nicotinic agonists. Similarly. the trans diaxial relationship between the quaternary nitrogen and acetoxyl group led to maximal tnuscarinic response and rate of hydrolysis by true acetylcholinesterase in a series of isomeric

CH3 H3C

H2

Extended

Quasi-ring

Acetytthotlne

A

AH.11 OH3

trans

0 H

CH3

2-Acotoxycyctopropyl trimethylammontum Iodide

trans

cis

3-Trlmethylammonlum-2-acetoxydecatins

Figure 2—17 a Acelylcholine conformations (only one each ol the two possible trans and cis isomers is

represented).

_A Chapter 2 • Plivsieoche,nieai Properties in Re!aiio,i in Iiiologii'a! ,tc:ion

3-trimethylarnmonium-2-ucetoxydecalins."' These results could be interpreted as either that acetykholinc was acting in a trans conformation at the muscarinic receptor and not acting in a cisnid conformation at the nicotinic receptor or that the nicotinic response is highly sensitive to steric effects of substitucnts being used to orient the molecule. This approach in studying the cholinergic receptor is covered in more detail in Chapter 17.

35

hihits l2to IS times more vasoconstrictor activity than( + )epinephrine. This is the classical three-point attachment model. For epincphrine. the ben,ene ring. benzylic hydroxyl. and protonated amine must have the stereochemistry seen with the (—) isomer to match up with the hydrophobic or aromatic region, anionic site, and a hydrogen-bonding center on the receptor. The 1 +) isomer (the mirror image) will not

align properly on the receptor.

Optical isomerism and Biological Activity The widespread occurrence of differences in biological activities for optical ai1sv,tn's has been of particular importance in

the development of theories on the nature of

drug—receptor interactions. Most commercial drugs are asymmetric, meaning that they Cannot be divided into symmetrical halves. While o and L isomers have the same physical properties. a large number of drugs are dir,szereo,nerie. meaning that they have two or more asymmetric centers. Diasicreomers have different physical properties. Examples are the diastereomers ephedrine and pseudoephedrinc. The

Pseudoeph.dr in.

Eph.dr In.

(Erythro conflgur.tlon)

(Thr.o configuration)

CH3.

—oil

former has a melting point of 790 and is soluble in water. whereas pseudoephedrin&s melting point is 118°, and it is only sparingly soluble in water. Keep in mind that receptors

DH

will be asymmetric because they are mostly protein, meaning that they are constructed from L-amino acids. A ligand fitting

the hypothetical receptor shown in Figure 2-18 will have to have a positively charged moiety in the upper left corner and a hydrophobic region in the upper right. Therefore, one would predict that optical isomers will also have different biological properties. Well-known examples of this phenomenon include (—1-hyoscyamine, which exhibits 15 to 20 times more mydriatic activity than (+ 1-hyoscyamine. and —)-ephedrine. which shows 3 times more pressor activity than ( + )-ephedrine. 5 times more pressor activity than + )pseudoephedrine. and 36 times more pressor activity than I—)-pseudoephedrinc. All of ascorbic acid's antiscorbutic properties reside in the (+) isomer. A postulated fit to epincphrine's receptor can explain why (—)-epinephrinc cx-

Phe 147

Anionic Site

Receptor (— ) .Epinephrine — more active

Frequently, the generic name indicates a specific stereoisomer. Examples include levodopa. dextroamphetamine. dexromethorphan. levantisole. dexmelhylphenidatc. and levothyroxine. Sometimes the difference in pharmacological activity between stercoisolners is dramatic. The dextrorotatory isomers in the morphine series are cough suppressants with less risk of substance abuse, whereas the levorotatory isomers (Fig. 2-19) contain the analgesic activity and significant risk of substance abuse. While the direction of optical rotation is opposite to that of the morphine series. dextropropoxyphene contains the analgesic activity, and the lern isomer contains antitussive activity. Figure 2-19 contains examples ol drugs with asymmetric

carbons. Some were originally approved as racemic mixtures, and later a specific isomer was marketed with claims of having fewer adverse reactions in patients. An example of the latter is the local anesthetic levohupivacainc. which is the S isomer of hupivacainc. Both the R and S isomers have good local anesthetic activity. hut the R isomer may cause depression of the myocardium leading to decreased cardiac output. heart block hypotension. bradycardia. and

B

25

Ic A

73

ventricular ari-hythmias. In contrast, the S isomer shows less cardiotoxic responses but still good local anesthetic activity. Escialopram is the S isomer of the antidepressant citalopram. There is some evidence that the R isomer, which contains little of the desired selective serotonin reuptake inhibition. contributes more to the adverse reactions than tines the

Lye

S isomer.

102

As dramatic as the above examples of stereoselectivity may be, sometimes it may not be cost-effective to resolve the drug into its stereoisomcrs. An example is the calcium

Figure 2—18 • Diagram of a hypothetical receptor site. show-

ing distances between functional groups.

36

WiL'.on

and Gj.wuld's 1 cxl book of Organic Medicinal and Phannacewical Chemistry

52) Dextromethorphan

Levomothorplian

cM3

$

Levopropoxypt3ene

IR

D.xtropropoxyphene

r "CM2

cM3

..CH2

CH2 R.S

NC

H2C1

CM,

CM2

/LM3 R.S-Buplvacalne Esdialopram

channel antagonist ver.ipamil, which illustrates why it is diflicult to conclude that one isomer is superior to the other. S-Verapamil is a more active pharmacological stereoisomer than R-verapamil, but the former is more rapidly metabolized by the first-pass effect. (First-pass refers to orally administered drugs that are extensively metabolized as they pass through the liver. Sec Chapter 4. S- and R-warfarin are metabolized by two different cytochrome P-450 isozymes. Drugs that either inhibit or induce these enzymes can significantly affect warfarin's anticoagulation activity. Because of biotransformations after the drug is administered, it sometimes makes little difference whether a racemic mixture or one isomer is administered. The popular nonsteroidal anti-inflammatory drug (NSAID) ibuprofen is sold as

Figure 2—19 • Examples of drug stereoisomers.

the racemic mixture. The S enantiomer contains the antiinflammatory activity by inhibiting cyclooxygenase. The R isomer does have centrally acting analgesic activity, but it is converted to the S form in viva (Fig. 2-20). In addition to the fact that most receptors are asymmetric.

there are other reasons why stereoisomers show different biological responses. Active transport mechanisms involve asymmetric carrier molecules, which means that there will be preferential binding of one stereoisomcr over others. When differences in physical properties exist, the distzibution of isomers between body fluids and tissues where the receptors are located will differ. The enzymes responsible for drug metabolism are asymmetric, which means that biological half-lives will differ among possible stereoisomers

Chapter 2 • Pliv.cko.hemii'aI Propertir.c in Relation to Uioiugital ,tction

0

"Cii

AH3

II

S-Ibuprolen

Metabolic Interconversion

CM3

CM3

t

_.CH,

R'Ibuprofen

Figure 2—20 • Metabolic interconversion of R- and S-ibuprofen

of the same molccule. The latter may be a very important sariable because the metabolite may actually be the active molecule.

Calculated Conformations It should now be obvious that medicinal chemists must obtaut an accurate understanding of the active conformation

of the drug molecule. Originally, molecular models were constructed from kits containing a variety of atoms of different valence and oxidation states. Thus, ihere would be carbons suitable fur carbon—carbon single. double, and triple bonds; carbon—oxygen bonds for alcohols or ethers and the carbonyl moiety: carbon—nitrogen bonds for amines. amides. imines, and nitrites: and carbons for three-, four-, five-, and larger-member rings. More complete sets include a variety of hcteroatoms including nitrogen. oxygen. and sulfur

37

crgy diagram is shown in Figure 2-21. Notice that some of the minima are nearly equivalent, and it is easy to move from one minimum to another. From energy diagrams. ii is difficult to answer the question. which of the ligand's low or moderately low conformations fits Onto the receptor? This question can he answered partially by assuming that lower energy conformations are more highly populated and thus more likely to interact with the receptor. Nevertheless, spe-

cific interactions like hydrogen bond formation and dipole—dipole interactions can affect the energy levels of different conformations. Therefore, the bound conformation of a drug is seldom its lowest energy conformation. Numberofeonlormers =

tangle Increment

(Eq. 2.30)

There are three common quantitative ways to obtain estimations of preferred molecular shapes required for a good fit at the receptor. The first, which is the oldest and considered the most acctir,uc, is x-ray crystallography. When propcr1)' done, resolution down to a few angstrom units can be obtained. This permits an accurate mathematical description

of the molecule, providing atomic coordinates in three-dimensional space that can be drawn by using a chemical graphics program. A serious limitation of this technique is the requirement for a carefully grown crystal. Some chemicals will not form crystals. Others form crystals with mixed symmetries. Nevertheless, with the newer computational techniques, including high-speed computers. large databases of x-ray crystallographic data are now available. These databases can be searched for structures. including substructures. similar to the molecule of interest. Depending on how close

match, it is possible to obtain a pretty good idea of the low-energy conformation of the drug molecule. This is a common procedure for proteins and nucleic acids after is

oht:tining the amino acid and nucleotide sequences, respec-

tively. Obtaining these sequences is now largely an automated process.

'rhere also is the "debate" that asks if the conl'ormation

in vartous oxidation states. These kits might be ball and stick, stick or wire only, or space filling. The latter contained attempts at realistically visualiting the effect of a larger atom such as sulfur relative to the smaller oxygen. The diameters

of the atoms in these kits are proportional to the van der radii, usually corrected fur overlap eflècts. In contr,ist. the wire models usually depict accurate intraatomic distances between atoms, A skilled chemist using these kits usually can obtain a reasonably accurate three-dimensional representation. This is particularly true if it is a moderately simple molecule with considerable rigidity. An extreme ex-

ample is a steroid with the relatively inflexible fused-ring

0

I

system. In contrast, molecules with chains consisting of sevcml atoms can assume many shapes. Yet, only one shape or confonsiation can be expected to lit onto the receptor. The

itumber of conformers can be estimated from EluatiOn 230. Calculating the global minimum, the losvest energy conformation, can be a difficult computational problem. Assume that there are three carbon—carbon freely rotatable single bondsthatare rotated in 10" increments, Equation 2-3fistates that there are 46.656 different conformations. A typical en-

120

180

240

Toelon Angie Figure 2—21 • Diagram showing the energy maxima and ima as two substituted carbons connected by a single bond are rotated 360° relative to each other.

38

Wilson and Gixvold.s Textbook of Organic Medicinal awl Phar,naceu,ical Che,nistry

found in the crystal represents the conformation "seen" by the receptor. For rigid molecules, it probably is. The question is very difficult to answer for flexible molecules. A common technique is to determine the crystal structure of a protein accurately and then soak the crystal in a nonaqueous solution of the drug. This allows the drug molecules to diffuse into the active site. The resulting crystal is reanalyzed using different techniques, and the bound conformation of the drug can be determined rapidly without redoing the entire protein. Often. the structure of a bound drug can be determined in a day or less.

Hecause of the drawbacks to x-ray crystallography, two purely computational methods that require only a knowledge of the molecular structure arc used, The two approaches are known as quai,nun nieehwucs and molecular mechanics. I3oth are based on assuniptions that (a) a molecule's threedimensional geometry is a function of the forces acting on the molecule and (F') these forces can be expressed by a set of equations that pertain to all molecules. For the most part, both computational techniques assume that the molecule is

in an isolated system. Solvation effects from water, which are common to any biological system, tend to be ignored, although this is changing with increased computational power. Calculations now can include limited numbers of water molecules, where the number depends on the amount

of available computer time. Interestingly, many crystals grown for x-ray analysis can contain water in the crystal lattice. High-resolution nuclear magnetic resonance (NMR) provides another means of obtaining the structures of macromolecules and drugs in solution. There are fundamental differences between the quantum and molecular mechanics approaches. They illustrate the dilemma that can confront the medicinal chemist, Quantum mechanics is derived from basic theoretical principles at the

atomic level. The niodel itself is exact, but the equations used in the technique are only approximate. The molecular properties are derived from the electronic structure of the molecule. The assumption is made that the distribution of electrons within a molecule can be described by a linear sum of functions that represent an atomic orbital. (For carbon. this would be s.p,,p,. etc.) Quantum mechanics is computa-

tion intensive, with the calculation time for obtaining an approximate solution increasing by approximately times. where N is the number of such functions. Until the advent of the high-speed supercomputers. quantum mechanics in its pare form was restricted to small molecules. In other words. it was not practical to conduct a quantum mechanical analysis of a drug molecule. To make this technique more practical, simplifying techniques have been developed. While the computing time is decreased, the accuracy of the outcome is also lessened. In general, use of calculations of the quantum mechanics type

in medicinal chemistry is a method that is still waiting to happen. It is being used by laboratories with access to large-

scale computing, but there is considerable debate about its utility because so many simplifying approximations must be made for larger molecules. In contrast, medicinal chemists are embracing molecular mechanics. This approach is derived from empirical observations. In contrast to quantum mechanics, the equations in molecular mechanics have exact solutions. At the same time. the parameters that are used in these equations are adjusted

to ensure that the outcome fits experimental observations. In place of the fundamental electronic structure used in quantum mechanics. molecular mechanics uses a model consist-

ing of balls (the atoms) connected by springs (the bonds). The total energy of a molecule consists of the sum of the following energy terms: stretching and compren,ing of he bonds (springs) bending about a central atom E: rotation about bonds van tier Waals' interactions electrostatic inter.Ictions

Each atom is defined (parameterized) in terms of these energy terms. What this means is that the validity of molecular mechanics depends on the accuracy of the pararneferitalion process. Historically, saturated hydrocarbons have proved easy to parameteri,e, followed by selective hetcroaioms such as ether oxygens and amines. Unsaturated systems. including aromalicity. caused problems because 01' the delo-

ealization of the electrons, but this seems to have been solved. Charged atoms such as the carhoxylate anion and protonated amine can prove to he a real problem, particularly

if the charge is delocalized. Nevertheless, molecular mechanics is being used increasingly by medicinal chemists to gain a better understanding of the preferred conformation of drug molecules and the macromolecules that compose a receptor. The computer programs are readily available and run on relatively inexpensive. but powerful, desktop computers.

In summary. quantum mechanics attempts to model the position or distribution of the electrons or bonds, while molecular mechanics attempts to model the positions of the nuclei or atoms. Quantum mechanics calculations are used commonly to generate or verify molecular mechanics parameters. Larger structures can be studied by use of molecular mechanics, and with simulation techniques such as molecular dynamics, the behavior of drugs in solution or even in passage through hilayer membranes can he studied.

The only way to test the validity of the outcome from either quantum or molecular mechanics calculations is to compare the calculated structure or property with actual experimental data. Obviously, crystallographic data provide a reliable measure of the accuracy of at least one of the lowenergy conformers. Since that is not always feasible, other physical chemical measurements are used for comparison. These include comparing calculated vibrational energies, heats of formation, dipole momnems. and relative conformational energies with measured values. When results are inconsistent, the parameter alues are adjusted. This readjustment of the parameters is analogous to the fragment approach for calculating oclanol/wamer partition coefficients. The values for the fragments and the accomnpanying correction factors are determined by comparing calculated partition coefficients with a large population of experimentally determined partition coefficients.

Three-Dimensional Quantitative Structure-Activity Relationships With molecular modeling becoming more common, the QSAR paradigm that traditionally used physicochemical descriptors on a two-dimensional molecule can be adapted to

Chapter 2 • Phvsjroche,,,kul Proper: k's in Relation

three-dimensional space. Essentially, the method requires knowledge of the three-dimensional shape of the molecule. Indeed, accurate modeling of the molecule is crucial. A reference (possibly the prototype niolecule or shape is selected against which all other molecules are compared. The original method called for overlapping the test molecules with the rek'rcnce molecule and minimizing the differences in overlap. Then distances were calculated between arbitrary locationson molecule. These distances were used as variables in QSAR regression equations. While overlapping rigid ring systems such as tetracyclines. steroids, and penicillins are relatively easy. flexible molecules can prove challenging. Examine the following hypothetical molecule. Depending

fir

liiologic'al Act ion

39

genetic code to determine the amino acid sequence. The parts of the receptor that hind the drug (ligand) can be determined

by site-directed mutagenesis. This alters the nucleotide Sequence at specific points on the gene and, therefore, changes specific amino acids. Also, keep in mind that many enzymes

become receptors when the goal is to alter their activity.

represented by X, a family of compounds represented by this molecule could have a variety of conlonrtations. Even when

Examples of the latter include acetylcholinesterase, monoamine oxidase. HIV protease. rennin. ACE, and tetrahydrofolate reductase. The starting point is a database of chemical structures. They may belong to large pharmaceutical or agrochensical tirms that literally have synthesized the compounds in the database and have them "sitting on the shelf." Alternatively. the database may be constructed so that several different chemical classes and substituent patterns are represented. (See discussion of isosterism in the next section.) The first

the conformations might he known with reasonable cer-

step is to convert the traditional or historical two-dimen-

tainty. the reference points crucial for activity must he identilied. Is the overlap involving the tetrahedral carbon important for activity! Or should the live-membered ring provide the reference points? And which way should it be rotated? Assuming that R5 is an important part of the pharmacophore.

sional molecules into three-dimensional structures whose intramolecular distances are known. Keeping in mind the prob-

on the sii.e of the various R groups and the type of atom

should the live-nternbered ring be rotated so that R5 is pointed down or up? These are not trivial questions. and successful 3D-QSAR studies have depended on just how the

investigator positions the molecules relative to each other. There are several instances in which apparently very similar structures have been shown to bind to a given receptor in differettt orientations.

Cl

R8

NH ¼'

(I Rd

There are a variety of algorithms for measuring the degree of confurmational and shave similarities, including molecuar shape analysis (MSA )I distance gcotnelry,'8 and molec-

ular similarity matrices.'9'20 Many of the algorithms use graph theory. in which the bonds that connect the atoms of a nmlecule can he thought of as paths between specific points on the molecule. Molecular connectivity is a commonly used application of graph theory.21 23

Besides comparing how well a family of molecules overlaps with a reference molecule, there are sophisticated software packages that determine the physicochemical parameters located at specific distances from (he surface of the tiolecule. An example of this approach is comparative molectilar field analysis (CoMFA). This technique is described in more detail in Chapter 3.

Database Searching and Mining As pointed out above, receptors are being isolated and cloned. This means that it is possible to determitie their struc-

tures. Most are proteins, which means determining their amino acid sequence. This can he done either by degrading the pmtein or by obtaining the nucleotide sequence of the structural gene coding for the receptor and using the triplet

lems of finding the . 'correct" conformation l'or flexible molecule, false hits and misses might result from the search. Next, the dimensions of the active site must he determined. Ideally. the receptor has been crystallized. ttnd from the coordinates, the intramolecular distances between what are assumcd to be key locations are ohtttincd. If the receptor cannot be crystallized, there arc methods for estimating the threedimensional shape based on searching crystallographic databases and matching amino acid sequences of proteins whose tertiary structure has been determined.

Fortunately, the crystal Structures of literally thousands of proteins have been determined, and their structures have been stored in the Brookhaven Protein Databank. It is now

known that proteins with similar functions have similar amino acid sequences in various regions of the protein. These sequences tend to show the same shapes in terms of ra helix, parallel and antiparallel forms. urns in the chain. etc. Using this information plus molecular mechanics parameters, the shape of the protein and the dimensions of

the active site can he estimated. Figure 2-18 contains the significant components of a hypothetical active site. Notice that tour amino acid residues at positions 25. 73. 102. and 147 have been identified as important either for binding the ligand 10 the site or for the receptor's intrinsic activity. Keep in mind that Figure 2-18 ix a two-ditnensional representation of a three-dimensional image. Therefore, the distances between amino acid residues must take into account the fact that each residue is above or below the planes of the other

three residues. For an artificial ligand to "dock." or lit into the site, six distances must be considered: A. Lys—Glu: B, Glu—Phe: C'. Phe—Ser: I). Ser—Lys: E. Glu—Phe: and F, Lys—Phe. In reality, not all six distances may be important.

In selecting potential ligands. candidates might include a positively charged residue (protonated amine), aromatic ring, hydrogen bond donor or acceptor (hydroxy. phenol, amine. nitro). and hydrogen bond acceptor or a negatively charged residue (carboxylate) that will interact with the aspartate, phenylalanine. scrine. and lysinc residues, respectively. A template is constructed containing the appropriate residues at the proper distances with correct geometries, and the chemical database is searched for molecules that fit the template. A degree of lii or match is obtained for each "hit."

Their biological responses arc obtained, and the tuodel for

40

Wilson and Gistold.c Textbook of Organic Medicinal and Pharmaceutical Chemistry

the receptor is further refined. New. better-defined ligands

sites. Robotic devices are available for this testing. Based on the results, the search for viable structures is narrowed,

may be synthesized. In addition to the interatomic distances, the chemical databases will contain important physicochemical values includ-

and new compounds are synthesized. The criteria for activity

ing partition coefficients, electronic terms, molar refractivity. pK4s. solubilities. and steric values. Arrangements of atoms may be coded by molecular connectivity or other to-

pological descriptors. The resull is a "flood of data" that requires interpretation, large amounts of data storage, and rapid means of analysis. Compounds usually must fit within defined limits that estimate absorption. distiibution, metabolism, and excretion (ADME). Chemical databases can contain hundreds of thousands of molecules that could be suitable ligands for a receptor. But, no matter how good the fit is to the receptor, the candidate molecule is of no use if the absorption is poor or if the drug is excreted too slowly from the body. An analysis of 2,245 drugs has led to a set of "rules" called the Lipinski Rule of A candidate molecule is more likely to have poor absorption or permeability if I. The molecular weight cxcecds 5(X) 2. The calculated octanol/water partition coefficient exceeds 5 3. There are more than 5 H-bond donors cxpre.ssed as the sum of 0—H and N—H groups 4. There are more than 10 H.hond acceptors expressed us the sum of N and 0 atoms

The rapid evaluation of large numbers of molecules is sometimes called high-throughput screening (Fig. 2-22). The screening can be in vitro, often measuring how well the tested molecules bind In cloned receptors or enzyme active

CheiukoJ tesled

1,, so in i'iIro

I

will be based on structure and physicochemical values. QSAR models can be developed to aid in designing new active ligands.

Alternatively, the search may be virtual. Again starting with the same type of database and the dimensions of the active site, the ability of the compounds in the database to

fit or bind is estimated. The virtual receptor will include both its dimensions and physicochemical characteristic. Keeping in mind that the receptor is a protein, there will be hydrogen bond acceptors and donors (serine, threonine. lyrosine), positively and negatively charged side chains (lysine, histidine, glutamic acid, aspartic acid), nonpolar or hydrophobic side chains (leucine, isoleucine, valine, alanine), and induced dipoles (phenylalanine, tyrosine). The type of groups that will be attracted or repulsed by the type of amino acid side chain is coded into the chemical database. The virtual screening will lead to development of a refined model for good binding, and the search is repeated. When the model is considered valid, it must be tested by actual screening in biological test systems and by synthesizing new compounds

to test its validity.

The term isoslerLsni has been used widely to describe the selection of structural components—the steric. electronic, and solubility characteristics that make them interchangeable in drugs of the same pharmacological class. The concept

Target Receptor

Eveiaad.a does

or ActiVe Sit.

ealfr4'by

Chemical Structure

I Chemical Structure I Database

I Database (Includes descriptors)

(Includes descriptors)

RsflnsModel

I Virtual Screening

I

—

1 I

Results

FIgure 2—22 a High-throughput screening.

j

Chapler 2 • l'hv.sjciohesnjea!

in Rehnir,n to

.4ilioii

41

of IsOstenslil has evolved and changed

in the years since its introduction by Langmuir in 1919/' Lang-

similar electronically, are sufficiently alike in their steric nature to be frequently interchangeable in designing new

muir. while seeking a cunctation that would explain similarities in physical properties for nonisomenc molecules, defined is issleres as compounds or groups of atoms having the same number and arrangement of electrons. Isosteres that were isoelectric (i.e.. with the same total charge as well as the Sante number of electrons) would possess similar physical properties. Forexample. the molecules N2 and CO both pox-

drugs.

54155 (4 total electrons and no charge and show similar physi-

propellics. Related examples described by Langmuir N4 . and NCO (Table 2-14).

were CO2.

With immcreaxed understanding of the structures of molecuks. less emphasis has been placed on the number of elec-

Compounds may he altered by isosteric replacements of atoms or groups, to develop analogues with select biological effects or to act as antagonists to normal metaholitcs. Each

series of compounds showing a specific biological effect must be considered separately, for there are no general rules

that predict whether biological activity will be increased or decreased. Some examples of this type follow. When a group is present in ti part of a molecule in which it may be involved in an essential interaction or may influence the reactions of neighboring groups. isosteric replace. ment sometimes produces analogues that act as antagonists.

trons involved, because variations in hybridization during bond formation may lead to considerable differences in the angles. lengths, and polarities of bonds formed by atoms

The 6-NH2 and 6-OH groups appear to play essential roles in the hydrogen-bonding interactions of base pairs during nucleic acid replication in cells. The substitution of the sig-

with the same number nt peripheral electrons. Even the same atom may samy widely in its structural and electronic charac-

nificantly weaker hydrogen-bonding isosteric sulfhydryl

t41nstics when it forms part of a different functional group. Thus, nitrogen is part of a planar structure in the nitro group hut forms the apex of a pyramidal structure in ammonia and

groups results in a partial blockage of this interaction and a decrease in the rate of cellular synthesis.

Similarly, replacement of the hydroxyl group of l)terolglutamic acid (folic acid) by the amino group leads to arni-

amine_s.

nopterin, a folate antimetabolite. Addition of the methyl

Groups of atoms that impart similar physical or chemical properties to a molecule because of similarities in size. dcclrotlegativity. or stereochemistry are now frequently referred to by the general term of iso.cwre. The early recognition that hen,.ene and thiophene were alike in many of their properties

group to the p-aminohcnzoate nitrogen produced methotrexate, which is used in cancer chemotherapy. for psoriasis. and as an onmunosuppressant in rheumatoid arthritis. As a better understanding of the nature of the interactions between drug-metabolizing enzymes and biological recep-

lcd to the tenim ring equim'aie;us for the vinylene group i—CH=CH—) and divalent sulfur (—S—). This concept has led to replacement of the sulfur atom in the phenothia,ine ring system of tranquilizing agents with the vinylene

tors develops, selection of isnsteric groups with particular electronic. solubility, and steric properties should permit the rational preparation of drugs that act more selectively, At

group to produce the dibenzodiazepine class of antidepressaul drugs (see Chapter 14). The vinylenc group in an aromatic ring system may be replaced by other atoms isosteric to sulfur, such as oxygen (luran) or NH (pyrrole): however. in stich cases, aromatic character is significantly decreased. Examples of isosteric pairs that possess similar steric and electronic configurations are the carboxylate (COO-) and

of the principles of isosteric replacement are aiding in the understanding of the nature of these receptors.

sulfonamide (SO.NRJ ions, ketone (C=O) and sulfone 0 = S = O groups. chloride (Cl and trifluoromethyl (CF3) groups. Divalent ether (—0—). sulfide (—S—f. amine

The field of drug design. particularly those aspects that are computer intensive. is increasingly being featured on Web pages. Faculty and students might hod it instructive to search the Web at regular intervals. Many university chemistry departments have organized Web pages that provide excellent linkages. Listed below are a small number of representative sites that feature drug design linkages. Some have excellent illustrations. These listings should not be considered any type of endorsement by the author, editors, or publisher. Indeed, some of these sites may disappear.

i—NH—). and methylene (—CU2—) groups, although dis-

TABLE 2-14 Commonly Used Alicyclic Chemical Isosteres 5

1!ni%aknm uton%s and groups

—OH

—('H 2)

—Hr

ti

—-i-—Pr

21.015 snd groups tm

12

(SI C

—F —Ct

—SH

—CH1—

—0--- -('ONI4R

--NIl—

—('OCH2R

{'02R

—S—

---COSK

Tnsalcrmt at&)rn.s und

SELECTED WEB PAGES

htlp://www.nih.gov/ (Search menns: QSAR: molecular modeling) hmtp://www.pharma.etht.ch/qsar/ tittpJ/www.scamag.eomllinks/deiaull.htmnt http://www.inih-jentm.de/IMAGE.htmt http://www.coopcr.edu/engiimcenngIchcmechcmn/monte.hmniI hltp:lltrimon.ps.toyaku.uc.jp/—dohashi/damabase/indexc.htmnl

http://www.clunel.edu/BioDcv/ommIgatlery.htm http://www.mmetsci.org/Science/Comimpchcnm/featurcI9.hmml

http://clogp.pomona.cdu/meiichcm/chenilqsar-tlh/index.html

ti V.ok. A

the same time, results obtained by the systematic application

5. B knlk Prcss,

Organic ('twmu54r) or l)nig lk.agn and 0mg AdioS..

htmp://www.mima.ss.edulmnicrobio/rasnmohlmndex2.htm

'191.

http:I/www.wcbmo.ncti

42

VII con

wtd Gixvold'.c l'extbrsok of Organie Medicinal a,ul Pharmaceutical Chentislrv

REFERENCES I. Cvum'ltrrmn, A..

and

Fraser,

T.: R.

Soc.

Edinburgh

25:151.

11(68- 869. 2. Hansch. C..

Leo, A.. and Hockman. D.: Exploring QSAR: Hydropho-

and Steric Constants. Washington. DC. American Chemical Socicly, 1995. 3. Ilansch. C.. and Lien. E. 3.: 3. Mcd. Chem. 14:6,33. 1971. -I. Dearden. S.C.. and George, E.: 3. Phann. Phamtacol. 31:S45P, 1979. 5. Kuhinyi, H.: The bilinear model. In Kuchar. M. (ed). QSAR In Design of Iiioactive Molecules. Barcelona. 1. K. Protr,. 1984. Ii. Kut'inyi, H.: 3. Med. Chcm, 20:625. 1971. 7. Free, S. M.. and Wilson, 3. W.: .1. Med. Chem. 7:395. 1964. M.. and Ccladnfk. M.: The use of Free-Wilson 8. Waio.er, K.. model on investigating the relationship between the chemical structure and selectivity of drags. In Kttchar. M. led.). QSAR in Design at Bioaclive Molecules, Itarcelona. J. R. Prous. 1984. 9. Krusowski. M.D.. Hung. X.. Hoplingcr. A. J.. and Harrison. N. l,.:J. Med. Chem, 45:32 It), 2002. Ill. Vcdani. A.. and DottIer. M.: 3. Med. Chem. 45:2139. 2002. II. Stuper. A. 3.. Hrtlggcr, W. E.. and Jurs, P.C.: computer Assisted Studies of Chemical Structure and Biological Function. New York. John Wiley & Sons.. 1979. 12. Baum. R.. and Borman. S.: Client. Eng. News 74:28, 996. 13. Gordon, F. M., Barrett. K, W., Dower. W. 3.. ci al.: 3. Med. Chcm. 37: bic.

1385.

994,

14. Baker. B. K.: 3. Pharm. Sd. 53:347. 19M. 15. Chinu. C. Y.. Long. 3. P.. Cannon. J. G.. and Armstrong. P. D.: 3. Phunnacol. tap. 'flier. 166:243. 1969. $6. Smisstnan. E.. Nelson. W.. Day. 3.. and LaPidus. 3.: 3. Med. Chem. 9: 45)4. 1966.

$7. Hopltnger, A. 1.. and Burke. 0.3.: Molecular shape analysis: a formalism to quantitatively estuhlislt spatial molecular similnrily. In Johnson. M. A.. Maggioru, G.M. (eds.). Cotlcepts and Applications of Molecular

Similarity. New York. Johit Wiley & Sons. 1990. 18. Srivastava. S.. Richardson. W. W.. Bradely, M. P.. and Crippen. 0. M.: Three-dimensional receptor modeling using distance geometry and

Voronoi polyhydra. In Kubinyi. H. (ed). 3D-QSAR in I)rug Design: Theory. Methods and Applications. Leiden, The Netherlands. ESCOM. 1993.

19. Good, A. C.. Peterson, 5. 3.. and Richards. W. G.: 3. Med. Chetti. 36: 2929.

24. Lipinski. C. A.: J. Pharmucol. Toxicol. Methods 44:235. 2000. 25. Lipinski.C. A.. Lombardo. F.. I)omiity. It. W.. and Feeney. P.3.: Ads. Drug Dcliv. Rev. 46:3, 20(11. 26. Langmuir. I.: 3. Ant. Cherts. Soc. 41:1543. 1919.

993.

20. Grunt, A. C.. and Richards. W. G.. l)rug mt. J. 30:371. 1996. 21. Kier, I.. B.. and Hall. L. H.: Molecular Connectivity in Chemislry and Drug Research. New York. Academic Press, 1976. 22. Kier. L. B..and Hall. L. H.: Molecular Connectivity itt Structure-Activity Analysis. New York. Research Stctdies Press (Wiley). 1986. 23. Bonchev. D.: Information Theoretic Indices 6r Characterication of Chemical Structures. New York. Research Studies Press (Wiley). 1983.

SELECTED READING Abraham. 0. lcd.): Burgers Medicinal Chemistry and Drug Discovery. 6th ed. New York. Wiley.mntersciettce, 2003. Albert. A.: Selective Toxicity, 7th ml. New York. Chapman & Hall. 1985. Dean, P. M. (ed): Molecular Similarity in Drug Design. New York, Chaptnan & Hull. 1995. Devillers. 3. and Balaban. A. T.. teds.): Topological Indices and Related Descriptors in QSAR and QSPR. Amsterdam. Gordon and Breach. 1999.

Frunke. K.: Theoretical drug design methods. In Nauta. W. T.. and Rekker. R. F. (cdx.). Pharmacochemisu'y Library. vol. 7. New York. F.lxevier. 19144.

GOner. 0. F. led.): Pharmacophore Perception. Development, and Use in Drug Design. Lu Jolla. CA. International University Line. 2000. Hanach. C.. and Leo. A.: Explonng OSAR. vol. I. Fundamentals and Applications in ('heniisrry and Biology. Washington. DC. American Chemical Society. 1995.

Keverling Buisman. J. A.: Biological activity and chemical structure. In Nautu, W. 1.. Rekker. R. F. teds,). Pharmacoclsemistry Library. s'ol 2. New York. Elscvier. 1977. Kier. I.. B.. and Hall. L. H.: Molecular Structure Description, the Electrutopological Stale. New York. Academic Press. 1999. Leach, A. R.: Molecular Modeling Principles and Applications. Essex. England, Longmun 1996. Leo, A.. Hanuch, C.. and Hoekman. D.: Exploring QSAR. vol.2. Hydropho.

bic. Electronic, und Steric Constants. Washington, DC. Antericun Chemical Society. 1995. Martin, Y. C.: Quantitalive drug design. In Grunewuld. G. (edt. Medicinal Research. vol. 8. New York. Dekker, 1978. Mutschler. F.. and E. cds.l. Trends in Medicinal Chemistry. Berlin. VCH Publishers. 1987. Olson. E. C., and Chrisnollersen. R. E.: Coutputer assisted drug design. In Cunistock. M. J. (ed.l. ACS Symposium Serier. vol. 112. Washington. DC, American Chemical Society, 1979. Rappd, A. K.. and Cusewit. C. 3.: Molecular Mechanics Across Chemistry. Sauxalito. CA. 1997. Silverman, K. B.: The Organic Chctnisrry of Drug Design and Drug Action. New York. Academic Press, 1992. Topliss. 3. G.: Quantitative Structure.Activity Relationships of Drugs. Medicinal Chemistry, A Series of Monrogruphs. vol. 19. New York. Academic Press. 1983.

Young, 0.: Computational Chemistry. A Practical Guide for Applying Techniques to Rcal World Prohletnt. New' York. Wiley-lntcrscicncc. 200$.

CHAPTER 3 Combinatorial Chemistiy DOUGLAS R. HENRY

The term f)arath/,'m s/si/i is an overused one. hut in the mid1980s a true paradigm shift occurred in the way new drugs are synthesized and screened for activity. Prior to then, most

drug compounds were synthesized in milligram quantities in a serial one-at-a-time fashion. After synthesis, the compound was sent to a biologist, who tested it in several in vitro assays and returned the results to the chemist. Based on the assay results, the chemist would apply sonic structure—activity relationship (SARI or use chemical intuition to decide what changes to make in future versions of the molecule to improve activity. Using this iterative process, a

use. In 1963. Merrifield introduced the efficient synthesis of peptides on a solid support or resin (Fig. 3-2).' This made

the rapid, automated synthesis of peptides possible, and earned Merrilield a Nobel Prize in 1984. A key feature of his approach is the attachment of a growing peptide chain loan inert polymer bead. tisually about 100 4um in diameter. composed of polystyrene cross-linked with divinyl bcnzcne. Such beads were originally designed for size exclusion chromatography. The beads can be immersed in solvents. washed, heated. etc.. and when the synthesis is complete.

tures per week. Since the yield of marketable drugs from

the beads can be filtered l'rorn solution, and the reaction products can be cleaved front the polymer. yielding pure products. A Hungarian chemist. Arpad Furka, realized that

compounds synthesized and tested is only about I in 10.0(X). the road to success has been a long and expensive one, taking 6 to 12 years and costing S5(X) to $800 million per drug. In the mid- 1980s. this approach to drug synthesis changed

Merrifield's approach could be extended to allow the sytitheciv of all possible combinations of a given set of amino acids in a limited number of steps. He accomplished this by splitting and remixing portions of the peptide-bound resin at each

dramatically with the introduction ol combinatorial chemistry. The drug discovery process becanic a highly parallel

step in the synthesis (Fig. 3-3). His description of the use of combinatorial chemistry to synthesize polypeptides appeared in the Hungarian patent literature in 1982. Apparently, it is the lirst literature reference to a combinatorial

chemist would be able to synthesize only a handful of struc-

one, in which hundreds or even thousands of structures could be synthesized at one time. Interestingly, biologists had for

some lime been using high-throughput screening HTS) to perform their in vitro assays, running assays in 96-well microtiter plates and even using laboratory robotics for pipetting and analysis. The bottleneck had become the synthesis of the compounds to test. Chemists realized that syntheses could also be conducted by using a parallel approach. The term conrb,,satoru,l chemistry was coined to refer to the par— aDd generation of all possible co,ubinaiions of substituents uc components in a synthetic experiment. Whereas the yield fmm a serial synthesis is a single compound. the yield from a

chemistry experiment.2 As seen in Figure 3-3. the advantage of split-and-mix syn-

thesis is that all 27 tripeptides can be synthesized in just three steps, instead of 27 steps. The disadvantage of this approach is that in the end, one obtains three mixtures of beads with tripcptides attached, rather than the pure compounds themselves. If activity is detected in one of the mix-

combinatorial synthesis is a chemical liltrar. Figure 3-I

tures, it becomes necessary to go back and resynthesize some or all of the structures in that mixture, to see which tripeptide is responsible for the activity. As we shall see, various methods for tagging and deconvoluting combinatorial libraries

shows two common types of chemical libraries—a generic

have been devised that reduce or eliminate the need for re-

library, based on a single parent or scaffold structure and multiplesubstituentsorresidues. and a mixture library, containing a variety of structure types. The total number of structures in alibrary iseitherthe product of the various nunibersofsubstitnents (for a generic library) or the total number of structures in a mixture. The goal of conihinatonal chemistry is to be able

synthesis.

to synthesize, purify, chemically analyze. and biologically test all the structures in the library, using a.s few synthetic cxperimenisas possible. This chapterdescrihes how combinatorial chemistry and HTS are being used in drug design and discosery to find new lead structures in a sluwter time.

HOW IT BEGAN: PEPTIDES AND OTHER LINEAR STRUCTURES Combinatorial chemistry was first applied to the synthesis of peptides, since a convenient method for the automated already in svidesprcad synthesis of these compounds

The first combinatorial chemistry experiments were applied to the study of epitopes—the short sequences of amino

acids responsible for antibody recognition and binding to proteins. Early researchers used solid-phase resin beads in vials. microtiter plates. colutnns, and porous plastic mesh "tea bags" They also used brush-like arrays of plastic pins. at the ends of which compounds could be synthesized. Other media that have been used include paper and polymer sheets and glass chips—basically anything that can immobilize a structure for the purpose of exposing it to reagents and solvents (Fig. 3-4). Peptides. of course, make poor oral drug molecules because they hydrolyze in the acidity of the stomach. As combinatorial methods were applied to the synthesis of drugs, a need developed for methods of generating small (molecular weight. $l billion in sales per year) going off patent in the next few years. Part of the problem has been the pursuit of only a few, highly profitable, therapeutic

targets. For example, there are at least seven Stalin cholesterol drugs on the market: the most prolitable one. Lipitor, currently collects about 57 billion in sales per year for its developer. Another problem has been the marketing of drugs that appeared to be safe, even throughout clinical

Chapter 3 a Combinatorial Chemistry riuls, hut were later found to cause serious and even fatal side effects (e'., Seldane and Baycol). There is tithe question that combinatorial chemistry has been effective in generating large numbers of lead structures. pharmaceutical companies began using combinatorial

chemistry to build up their in-house libraries of structures that could be "mined" for activity against newly discovered receptors. A typical pharmaceutical firm has access to infor-

mation on 10 to 20 million structures from commercial sources (various chemical software vendors and the Amen-

TABLE 3-3 Examples of Lead Structures Obtained by Combinatorial Chemistry

Structure

Source

Target

Mechanism

Merek

III

Block Strut integration

SinhkKiine leeeliam

ci

59

I intcgruse

Human Scrotonin receptor

AntagoniM: cognithe

CF3

Abbou

intcrlcukin-2

Cytokine Inititsitirm

CF3

Plizer

Earnesyl trunufetase a

Inhibition

Parkc Davis

KDO-8-P synthetasc

N—N

Cl

Inhibition; antibiictorijl

60

lViI.con and Gici'old's Textbook of Organic Medicinal and Pharmaceutical Chemistry

can Chemical Society Chemical Abstracts Service). In addi-

Journals

tion. large companies have their own multimillion-compound databases. Golehiowski et describe how lead structures with a wide variety of activity have been obtained with use of combinatorial chemistry. Sonic examples are shown in Table 3-3, demonstrating the variety of structural types that have been generated. An industry perspective pub-

lished in 2001 reported 46 compounds in human clinical trials that originated from HTS of libraries that were identifled between 1992 and What can be argued is whether the goal of generating lead structures is sufficient, in light of an increasing rejection rate of candidate drugs in clinical trials, caused by side effects and other ADMEI'-related failures. Most researchers would

agree that we need to predict the "drugability" of a lead better before much testing, if any, is done. As mentioned in the section on virtual screening, much work is being devoted

to the development of better in vitro and computational methods for predicting ADMET properties. Alternatives to combinatorial chemistry arc appearing in the literature. An

examfle is the "non-combinatorial" approach of Everett et al. These authors argue that the goal of combinatorial chemistry should be the quality, not the quantity, of leads. Some trends that are appearing in the literature include (a) smaller libraries, a few thousand carefully selected structures rather than 250,000 hastily designed ones; (b) more attention to ADMET properties in the early phases of drug discovery; (c) miniaturization of syntheses and assays, using ,nicrofluidics and nanoiechnologv. both for speed and to conserve resources; and (d) an integration of genomic and combinatorial chemistry technology for better use human genome information in the design of new drugs.46 Most chemists agree

that combinatorial chemistry, after 20 years of evaluation. is a vital, but not the only, implement in the drug discovery toolkit that should be used. Like other tools, it can be applied intelligently to great benefit, or it can be misused,

RESOURCES FOR COMBINATORIAL CHEMISTRY

Combinatorial

Chemist re and High-Tl,rou.c.hput Screen ing—Bentham Publishers Drug Discovery Today—Reed Elsevier Journal of Chemical Information and Computer Sti ences—American Chemical Society

Journal of Combinatorial Chen,isirs—American Cheinica Society

Modern Drug Discovery—American Chemical Society Molecular Diversitv—Kluwer Nature Reviews Drug Discovery—Nature Publishing Group Trends in Biotechnology (T1BT&'H)—Elscvicr

Videos Che,nicai Diversity: Applications of Computational Approaches Washington, DC. American Chemical Society. 1995. Chemical Diversity: Synthetic Techniques of Co,nbinatoria, Chemi,csry. Washington. DC. Anerican Chemical Society 1995.

Web Sites lutp://lvsvw.comhi.web.com—Corporate-sponsored web portal. Accessed Dec. 3, 2002. http://www.combkhent.neilhonte/login.a.sp—Recent develop. menu.. Accessed Dec. 3. 2002. hsrp://www.contbinarorial.com—Weh site for The Combinatorial Index text. Accessed Dcc. 3, 2002. hup://www.geocities.eo,n/ResearchTriangle/Lab/4688/ combinatorial chen,istrv.l,tm—llnofficial Combinatorial Chemistry Web site. Updated Mar. 5. 2002.

http://wwiv.microarrays.org—tjnivcrsity of Califomia at San Francisco site. Accessed Dcc. 3, 2002.

COMBINATORIAL CHEMISTRY TERMINOLOGY The following terms are some of the most common used in combinatorial chemistry and HIS. More complete glossaries can be found in Beck-Sicklinger. A., and Weber. P.: Combi.

natorial Strategies in Biology and Chemistry. New York. Beck-Sicklinger. A.. and Weber. P.: Combinatorial Strategies in Biology and Chemistry. New York. John Wilcy & Sons. 2002. (The finest short introduction available) Bunin. B. A.: The Combinatorial Index. New York, Academic Press, 1998 (a comprehensive, chemistry-oriented reference). Crarnik. A. W.. and DeWitt. S. H. (eds.): A Practical Guide to Combinatorial Chemistry. Washington. DC. American Chemical Society, 1997. Fennin. H.. Combinatorial Chemistry—A Practical Approach. Oxford. UK. Oxford University Press. 2000. (Laboratory experiments) (Those. A. K.. and Viswanadhan. V. N.: Combinatorial Library Design and Evaluation. Principles. Software Tools, and Applications in Drug Discovery. New York, Marcel Dekkcr, 200!. Gordon, E. M., and Kerwin, J. J. F. (eds.): Combinatorial Chemistry and Molecular Diversity in Drug Discovery. New York, Wiley-Lies, 1998. Terrett. N.: Combinatorial chemistry. In Compton, R. G.. Davies. S. 0.. and Evans. J. (edt.). Oxford Chemistry Masters. Oxford. UK. Oxford University Press. 1998. (A brief, highly readable introduction)

John Wiley & Sons. 2002, and in MacLean. D., et al.: Glos-

sary of terms used in combinatorial chemistry. I. Comb. Chem. 2:562—578. 2000. ADMET (also ADME. ADMET-FK): The collection of a mole. cule's properties related to absorption, distribution. meiabolism. excretion, toxicity, and phartniscokinetics, These facwrs are being increasingly considered in combinatorial library de-

sign, to yield molecules that will be more suitable as Aptasner: RNA molecule that displays specific binding to a target, usually a protein. Aptamers arc often used in rays in place of antibodies, to bind peptide ligands. Array synthesIs: The form of parallel synthesis in which the reaction vessels are maintained in a particular spatial arrange. ment, such as a grid in a microtiter plate. Such arrays generated

on a microscopic basis are termed a spatially addressable library. Backbone: A linear scaffold to which suhstituents are attached. Common backbones include the a carbon backbones of pep. tides and peptoids. Bead: A spherical particle of solid support. Typically 50 to (K)

Chapter 3 . ('o,nbi,,awrio! Chcn,i.un par or dianreter. they swell in solvent. allowing access by synthetic reagents for reaction, washing. etc. The loading on head is the amount of synthetic target that can be attached To ii sinnlc head, which is in the nanomolar range. Binary encoding: Encoding technique of a library based on the presence or absence of tags on a bead. Thus, the sequence 01 ItCh would encode thc presence of three of six possible tugs. The number of combinations that can he encoded is 2'. where it is the number of positions in the string. Binning: A computational procedure to allow selecting chciiiicul structures across a wide range of diversity. The structures are into bins on the basis of common physical or chemical structures.

Building block: One of a set of interchangeable reagents that can be used in the synthesis of a generic library. Capacity: Theoretical amount of material that could be atiached toa bead. Because of steric hindruncc of the synthetic target. it may he greater than the actual amount. Capillary electrophoresis: Method of separating components of a nrixture by placing the mixture at one end of a capillary Oiled with gel. A continuous gradient of electronic charge across the capillary causes the components to separate. much like a chmmatograpliic separation but based on charge, size. and shape of the molecules.

Cleavage: The process of releasing a compound from a solid support, allowing assay or analysis in solution. Special reagents or even enzymes may he used to release the compound without reacting with or ahienng it.

Clinter analysis: Statistical or pattern recognition technique to group a set of structures into ' natural" groupings or clusters tin the ha.sis of physicochemical or structural properties. It is similar to binning in its result, and both methods are cornmanly used to select a representative sample of structures, either for screening or as building blocks for combinatorial synthesis.

CombInatorial: Relating to combinations of objects. Combinatorial chemistry: Using a combinatorial process to prepare sets of compounds from building blocks. Combinatorial lIbrary: A set olcompounds prepared by combinatorial chemistry.

Cross-linking: The property of a polymer used in a solid SUpport such that long strands of polymer are interconnected at various points by relatively short sequences—much like rungs on a

61

A directed library lies midway between an initial e.qth;ra:i.-nr library and a final libr,irv in its size and overall diversity. Diversity: The "unrelatedness" of a set of, for example. building blocks or members of a combinatorial library, Measured using physicochemical orctructural descriptors, a set with high diversity spans a larger fraction of "chemical space." Cluster analysis is one technique used to quantify diversity. Dynamic library: A mixture of compounds in a dynamic cqui. lihriutn with, for example, a synthetic process. If a receptor

is introduced into the system, the equilibrium will shift to produce mote of the compounds that bind tightly with the receptor.

Encoding: The process of adding a chemical or electronic tag

to a bead for the purpose of "recording" the sequence of reaction steps to which the bead has been exposed. By th'-oding the resulting tag, perhaps by treating a DNA tag with polymcr-.tse chain reaction and analyzing the oligonucietrtide.

the exact nature of the synthetic target on the bead can be determined.

Enumeration: The process of explicitly describing all of the specific structures that a generic structure or library contains.

Epitope: The region of a protein strand that is rccogtiized by an antibody.

Fingerprint: An army of numbers In1, nj.. -. ) that numerically represents a given structure as values of physicochemical or structural descriptors. Commonly, the ttutnbers are binary It) or I). but they may also be counts (whole numbers) or values. Flow cytometry: Technique characterizing or separating par. tides such as beads or cells, often on the basis of their tluores-

cence. Used to separate beads that have biologically active molecules attached.

Fluorous synthesis: An approach to solution-phase synthesis that uses highly fitiorinated compounds as soluble supports for combinatorial chemistry. The addition of water or organic solvents causes a phase separation of the fluorinated support for subsequent cleavage of the synthetic target structure. Generic structure: General structural formula of a library. consisting of a .waffold(parent structure) pius rt'.cidue's (K groups). A simple example is

Genetic algorithm: Method of library design by selecting sub. stituents for a library in a stepwisc fashion, bused on the fitness of the resulting library for some purpose (e.g.. biological activity). At each step, the substituents arc modified by use of the genetic principles of recombination. crossover, mutation. etc.

flexible ladder. Cross-linking affects the properties of the polymer, including its ability It) swell in different solvents. Decode: To "read'' a chemical or electronic tag attached to a bead or other solid support, for the purpose of determining the of reaction steps that were applied to the given

Selection of the "fittest" conrbinatiot,s of substituenis yields a library thai is locally optimal for the given purpose. Green fluorescent protein (GFP): A protein isolated fromjelly-

head. This allows determining the composition of the synthetic

Itch that has its own fluorescence. It can be modified at various

target on the head,

l)econvolute: To make the results of a combinatorial experiment less complex, usually by backtracking and reanalyzing or resynthesizing a subset of the structures iii the library. The goal of deconvolution is to determine which of a mixture of compounds in actually responsible for activity. Dendrimer: A polymer having a very highly branched structure. Dendrimers can be used in place ol' solid supports for attachment of synthetic targets, and then they can be separated by ming size exclusion chromatography. Descriptor: A numerical representation of a molecular property, cithera bulk property (like log P) ora two-dimensional (2D) or three-dimensional (3D) structural property. When descriptors encode the presence or absence of a property, they are usually represented by Is and Os. and the collection of descriptors is called a fingerprint of the molecule, Directed (focused) library: A library that uses a limited number of building blocks chosen on the basis of information or some hypothesis that defines the functionalities needed for activity.

positions to generate molecules that fluoresce at different wavelengths. The DNA for this protein can be inserted into the genomes of cells to give them a fluorescent label. High-throughput screening (HTS): The process for rapidly assessing the activity of samples from a combinatorial library or other compound coliection. usuaily done by running parallel

assays in plates of 96 or more wells. A screening rate of 100.000 assays per day is termed ul:ra/sigh-throughpui screening. Hit: A compound that has some required level of activity. HPLC: High-performance liquid chromatography. Solvent is pumped under high pressure through a chromatographic columis containing a very finely divided support. The compounds in the mixture separate according to their affinity for the support and elate from the column at different times, to be detected by use of sonic optical or even mass spectronietric detector (HPLC-MS), In sillco screening: See i'iriual screening. Lead compound: First compound in the development of a drug

62

Wilson and Gisi'ald's Textbook of Organic Medicinal and Pharmaceutical Chemistry that has the desired biological and physicochemical properties. It typically has micromolar potency, and by optimizing various

positions of the molecule, the potency can be increased to nanomolar. at which point it would be considered for drug candidacy.

Library: A collection of structures, either a generic library (based on some scaffold plus multiple residues) or a mixture library (containing diverse scaffolds). The number of specific structures in a library is either the product of the numbers of residues possible at each variable position (for a generic Iibrary) or simply the sum of the number of structures (rot a mixture library).

Linker: A chemical chain that connects the solid or soluble support to the synthetic target in a combinatorial experiment.

The linker is decomposed when the desired compound is cleaved from the support.

Llplnski "rule of live": A set of criteria for predicting the oral bioavailability of a compound on the basis of simple molecular

properties (molecular weight. upted Up,

app. 02A. a213. 02C'.

02

Dopaminc

D1.D2

D1.D2',D3.D4.D5

Prostaglandin

El'1. El'2, EP1

El'1, El'2.

Nerve growth factor receplor

TrkA.'TrkB, TTIIC

Receptor tyrosine kinase ncurolxuphiris

El'4

DNA binding Estrogen

Estrogen receptor

ERRI. ERR2

Thyroid hormone

Thyroid honnone receptor

TRa,

Retinoic acid

Retinoic acid receptor

RARa.

(ilycinc

Glycinc and/or strychnine receptor

up. a2,

GAI3A4

GABA and/or beneodiazepine receptor

Ligund.aclivatcd channels (muitisubunit)h

a2. Op.

a*. a., (rnullisobpinit)5

revnptor hetcrogencily. inKNA .p!icine creates Only the hehruyrncny Iigltnd.hrnding subunit is Ii.,Icd.u mului.ubunpt stmruufc combined with the hctceogetepty oliheother subunits emotes, vciy lunge numbcro(ps Icilitlit sUhiSl'.,..

physiology of the adrenergic receptors and of developing drugs that can selectively interact with these subtypes. For example, in the case of the a2-agonist p-aminoclonidine, an agent used to lower intraocular pressure (lOP) in the treatment of glaucoma, it may now be possible to explain some of the drug's pharmacological side effects (e.g.. bradycardia and sedation> by invoking interactions with the additional receptor subtypes. Of considerable interest is the possibility that these pharmacological effects (i.e., lowering of lOP, bradycardia, and sedation) are each mediated by

one of the three different cz2-receptor subtypes. If this is true, it might be possible to develop a subtype-selective a2agonist that lowers lop but does not cause bradycardia or sedation. Likewise, it might even be possible to take advan(age of the pharmacology and develop a2-adrenergic agents that selectively lower heart rate or produce sedation. The discovery of subtypes of receptors and enzymes by molecular cloning studies seems to be the rule rather than

the exception and is offering a plethora of potential new drug targets (Table 6-4). To note just a few: 5 dopamine receptor subtypes have been cloned, replacing 2 defined pharmacologically (Chapter 15); 7 serotonin receptor subtypes have been cloned, replacing 3; 4 genes encoding recep-

tors for prostaglandin E2 have been isolated, including 12 additional alternative mRNA splice variants; and 3 receptors for nerve growth factor have been cloned, replacing I.

from more complex native biological systems. There is a reason for this. A newly identified protein can be expressed

in isolation. Even for closely related enzyme or receptor subtypes, heterologous expression of the individual subtype can potentially provide data that are specific for the subtype

being expressed, whereas the data from native biological systems will reflect the summation of the individual subtypes that may be present. The potential advantage of heterologous expression is

lustrated in Figure 6-9 for the interaction of a drug with multiple binding sites. In panel A. which can represent 11w data obtained from a native biological system, the data air complex, and the curve reflects interactions of the drug with two populations of receptors: one with high affinity. rcpre. senting 50% of the total receptor population, and one with low affinity, representing the remaining 50%. The individual contributions of these two populations of receptors are mdicated in panel B, which could also reflect the data obtained if rDNA encoding these two receptors were expressed mdi vidually in a heterologous expression system. Although in some cases the data, as in panel A. can be analyzed with succes.s. frequently they cannot, especially if more than two subtypes are present or if any one subtype makes up less than 10% of the total receptor population or if the of the drug for the two receptor populations differ by less than 10-fold. Another important reason for integrating heterologous expression into drug-screening strategies is that data can usu-

The combination of the heterologous expression of cloned DNA, the molecular cloning of new biological targets, and

ally be obtained for the human target protein rather than an animal substitute. This does not mean that organ prepara tions or animal models will be totally replaced. For the purposes of the identification of lead compound.s and the

the ability to manipulate gene sequences has created power-

zation of selectivity, affinity. etc.. however, the use

ful new tools that can be applied to the process of drug

recombinant expression systems provides some obvious ad-

discovery and development. In its most straightforward application, the ability to simply express newly identified receptor protein targets offers a novel means of obtaining information that may be difficult, or even impossible, to obtain

vanlage.s.

NOVEL DRUG-SCREENING STRATEGIES

By combining heterologous expression with novel functional assays, it is possible to increase both specificity and throughput (the number of compounds that can be screened

Chapter 6 • Biozech,wlogy and Drug Discm'ery

100

a

171

cAMP response element (CRE). This is a specifically defined sequence of DNA that is a binding site for the cAMP response element-binding (CREB) protein. In the unstimulatcd condition, the binding of CREB to the CRE prevents

multiple binding

80

lsmntenschi

the transcription and expression of genes that follow it (Fig. 6-10). When CREB is phosphorylated by cAMP-dependent protein kinase (PKA). however, its conformation changes.

permitting the transcription and expression of the down2:

°' -14

-12

-10

-8

6

-4

log (Drug) (M)

A 100

analyzed as singe-site interactions 60

Ut

C

dent fashion if it is placed downstream of a CRE, using rDNA techniques. If the products of the expression of the

50%

20

stream gene. Thus, increases in intracellular cAMP, such as those caused by receptors that activate adenylyl cyclase (e.g., 48-adrenergic, vasopressin. and many others), will stimulate the activity of PKA. which, in turn, results in the phosphory. lation of CREB and the activation of gene transcription. In nature, there are a limited number of genes whose activity is regulated by a CRE. Biologically, however, the expression of almost any gene can be regulated in a cAMP-depen-

\

\

,.,., 42

'10

50% low aitnity

I3nM

tosidase are three examples of potential "reporter genes"

r -8

-6

-4

log [Drug)

B

downstream gene can be easily detected, they can serve as reporters for any receptor or enzyme that can modulate the formation of cAMP in the cell. The genes encoding chloramphenicol acetyl transferase (CAT), luciferase, and f3-galac-

Figure 6—9 • Convoluted data from binding to multiple recepor sobtypes versus classic mass action.

Nrunil time). For example, reporter genes have been develirpcd that ro.pond to a variety of intracellular second messengru. ssch as the activation of guanine nucleotide-binding pwtems 4G proteins), and levels of cAMP, or calcium. One to the development of novel functional assays inwIves the use of promoter regions in DNA that control the

of genes. This approach is exemplified by the

whose products can be easily detected. Sensitive enzymatic assays have been developed for all of these enzymes; thus

any changes in their transcription will be quickly reflected by changes in enzyme activity. By coexpressing the reporter gene along with the genes encoding receptors and enzymes that modulate cAMP formation, it is possible to obtain very sensitive functional measures of the activation of the coexpressed enzyme or receptor. Another example of the use of a reporter gene for highthroughput drug screening is the receptor selection and amplification technology (r-SAT) assay. This assay takes ad-

vantage of the fact that the activation of several different classes of receptors can cause cellular proliferation. If genes for such receptors are linked with a reporter gene, such as

ORE-binding Protein (CREB)

off

,7CRE

Reporter Gene

CAMP Response Element

r

Figure 6—10 • Activation of transcripb1 a CAMP response element (CRE) o phosphorylated by CAM P-depenprotein kinase.

I

CRE

Reporter Gene

172

Wilson and Gi.c void's Texthook of Oria,iic Medicinal and Pharmaceutical Che,uistr.

/3-galactosidase, the activity of the reporter will be increased as the number of cells increase as a consequence of receptor

activation. Initially, a limitation of this assay was that it only worked with receptors that normally coupled to cellular by making a mutation in one of the secondmessenger proteins involved with the proliferative response, however. it was possible to get additional receptors to work in

this assay. This second-messenger protein. Gq. was

cloned, and a recombinant chimera was made that included

part of another second messenger known as C. In native cells, receptors that activate G1 arc not known fur their stimulation of cell proliferation, but when such receptors are coexpressed in the r-SAT assay with the chimeric C5. their activity can be measured,

A similar strategy involving chimeric proteins has been used for receptors whose second-messenger signaling pathways are not clearly understood. For example, the develop-

ment of potential therapeutic agents acting on the human growth hormone receptor has been difficult because of a lack of a good signaling assay. The functional activity of other receptors that arc structurally and functionally related to the growth hormone receptor can be measured, however. in a cell prolilerauon assay. One such receptor that has been cloned is the murine receptor for granulocyte colony-stimu-

lating factor (G-CSF). By making a recombinant chimeric receptor containing the ligand-binding domain of the human growth hormone receptor with the second-messenger—coupling domain of the murcin G-CSF receptor, it was possible to stimulate cellular proliferation with human growth hormone. In addition to providing a useful pharmacological screen for human growth hormone analogues, the construction of this chimeric receptor provides considerable insight into the mechanism of agonist-induced growth hormone receptor ac-

tivation. The growth hormone—binding domain is clearly localized to the extracellular amino terminus of the receptor. while the rransmembrane and intracellular domains are implicated in the signal transduction process. It was also determined that successful signal transduction required receptor dimerization by the agonist (i.e.. simultaneous interaction of two receptor molecules with one molecule of growth hormone). On the basis of this information, a mechanism-based strategy was used for the design of potential antagonists. Thus, human growth hormone analogues were prepared that were incapable of producing receptor dimerization and were found to be potent antagonists.

crated by an infected cell line, or introduced by animal serum. Purification of a rDNA protein while maintaining the factors that keep it in its active three-dimensional conforma. tion from this mixture may be difficult because each step must be designed to ensure that the protein remains intact and pharmacologically active. Assays must be designed that allow the activity of the protein to be assessed at each purification step. Consequently, the structure and activity of the recombinant protein must be considered at all stages of puti.

fication. and assays must be conducted to measure the amount of purified, intact protein. A general scheme for purification of a rDNA protein is as follows:95

• Particulate removal. Particulates may be removed by centrifugutioil. tiltration. ultrafiltration, and tangential flow filtration. Virus particles may be inactivated by heating if the rDNA peptide can tolerate the procedure. • concentration. The volume of the mixture is reduced, which increases the concentration of the contents. Often. conccntrulion is achievable by the filtration step, especially if ultrafiltu. lion is used.

• Initial purification. l'he initial purification of the mixture is sometimes accomplished by precipitation of the proteins. using a slow. stcpwisc increase of the ionic strength of the solution (salting out). Ammonium sulfate isa typical salt that can be used in cold, aqueous solutions. Water-miscible organic solvents such as trichloroacetic acid and polyethylene glycol change the dielectric constant of the solution and also effect

precipitation of proteins. • Intermediate purification. In this stage, the proteins may be dialyzed against water to remove salts thai were used in the precipitation step. Ion exchange chromatography is used to effect a somewhat crude separation of the proteins based on their behavior in a pH or salt gradient on the resin. Anothci step that may be taken is size exclusion (gel filtration) chroma-

tography. Gels of appropriate molecular weight cutoffs can yield a somewhat low-resolution separation of proteins of desired molecular weight. If a native bacterial protein that has been corned this far is nearly the same molecular weight as

the rONA protein, no separation will occur. • Fi,,al purification. Final purification usually involves the use of high-resolution chromatography, typically high-perfw. mance liquid chromatography. An abundance of commercial stationary phases allows various types of adsorption Chromatography (normal and reversed phase), ion exchange chroma-

tography. immunoaffinity chromatography, hydrophobic interaction chromatography, and size exclusion chin. matography. The protein fractions arc simply collected when they elute from thc column and are concentrated and assayed

PROCESSING OF THE RECOMBINANT PROTEIN Processing the fermentation contents to isolate a recombinant protein is often a difficult operation, requiring as much art as science. In the fermentation broth are whole bacterial cells. lysed cells, cellular fragments. nucleotides. normal bacterial proteins, the recombinant protein, and particulate medium components. If a Gram-negative bacterium such as E. coil has been used. lipopolysaccharide endotoxins (pyrogens) may be present. When animal cell cultures are used, it is commonly assumed that virus particles may be present. Viruses can also be introduced by the culture nutrients, gen-

for activity. • Sterilization and formulation. This step can be accomplished by ultrafiltration to remove pyrogens or by heating ii the protein can withstand this. Formulation might involve reconstitution into stable solutions for administration or determining Its optimum conditions for stability when submitting for clinical trials.

Complicating factors include (a) proteins unfolding into an inactive conformation during processing (it may not be possible to refold the protein correctly) and (b) proteases that are commonly produced by bacterial, yeast. and mammalian

cells, which may partially degrade the protein.

Chapter 6 • Rioicrhno!ogv and Drug DLsrvrerv

PHARMACEUTiCS OF RECOMBINANT DNA (rDNA).PRODUCED AGENTS 'DNA ittethods have facilitated the production of very pure.

useful prolcins. The physicochemical and pli.innacetitical properties of these agents are those of prosshiclt means that pharmacists must understand the

hemistry land the chemistry of instability) of proteins to core, handle. dispense, reconstitute, and administer these drugs. Instabilities among proteins may be physical nt chentical. In the former case, the protein might stick to vessels or flocculate, altering the dose that the patient will receive. In the latter case, chemical reactions taking on the protein may alter the type or stereochemistry 1 the amino acids, change the position of disulfide bonds, dcait' the peptide chains themselves, and alter the charge disuihution of the protein. Any of these can cause unt'olding denaturation) of the protein and loss of activity, rendering lie molecule useless as a drug. Chemical instability can be a rnihkm during the purification stages of a protein, when he ntniecule might be subjected to acids or bases, but insta-

could occur at the point of administration when, for esainpk. a lyophilized protein is reconstituted. The pharma-

cit must understand a few concepts of the chemical and l!iscal instability of proteins to predict and handle potential priblents.

Chemkat Instability of Proteins'7 see Figure 6-lI.

Hydrolytic reactions of the peptide bonds can

•

breuk the polymer chain. Aspauiate residues hydrolyze 100 i;nCs faster in dilute acids than do other amino acids under the same conditions, As a general rule of pcptidc hydrolysis.

AipPru > Asp.X or X-Asp bonds. This property of Asp is due to an autocatalytic Ilinction of the Asp side chain eartmsyl group. Ann. Asp, Gin, and Glu hydrolyze exception. easily if they occur nest to Gly. Ser, Ala, and Pro. Within these groupings, Asn and Gin accelerate hydrolysis more at

tow gIl. while Asp and Glu hydrolyze mail readily at high gil. sties the side chain carboxyl groups are ionized. • Dciridwinn. Gin and Asn undergo hydrolytic reactions that deamidate their side chains. These reactions convert neutral amino acid residues into citargcd ones. GIn is converted to Glu and Ann to Asp. The amino acid type is changed. hut the chain is nut cleaved. This process is..cffcctivcly. primary isOnltntation. and it may influence biological activThe deamidution reaction of Asn residues is accelerated under neutral or alkaline pit conditions. A five-mcmbcred mite intcrmediate formed by itnramoleculur attack of ihe nitrogen atom on the carhonyl carbon of the Asn side chain

the accelerant. The cyclic imide spontaneously hydrolyzes in give a mixture of residue.s—the aspairtyl peptide and an iso tigsi.

• Raeernt:nthn. Base-catalyzed raccmizotion reactions can

•wcur iii any of the amino acids except glycine. which is aehir.d. Rucemitutions yield proteitis with mixtures of .- and n-amiD,, acid configurations. The reaction occurs following the abstraction uf the u.hydrogen from the amino acid to fonn acarhanion. As should be expected, the stability of the carban-

in controls the rate of the reaction. Asp, which undergoes rjxmioation via a cyclic innide intermediate, racemizes 105 limes laster than free Asn. By comparison, other amino acids

173

in a protein raccmize about 2 is, 4 times laster than their free counterparts.

• 8.Elirninasion. Proteins containing Cys. Ser. Thr. Phe. and Lys undergo facile n-elimination in alkaline conditions that facilitate formation of an o carbunion. • Oxidation. Oxidation can occur at the sulfur-containing amino acids Met and Cys and at the aromatic amino acids His, Trp. and Tyr. These reactions can occur during protein processing as welt as in storage. Methionine (CH,-S-R) is oxidizable at

low pH by hydrogen peroxide or molecular oxygen to yield a sulfoxide (R.SO.CH,) and a sullonc The thiol group of Cys (R-SH) can undergo successive oxidation to the corresponding sulfcnic acid (R-SOH). disulf'tdc (R.S.S. RI. suluinie acid (R-SOH). and sulfonic acid (R-SO5H). A number of factors, including pH. intluence these reactions. Free —SF1 groups. can be converted into disult"tde bonds (-S. S-i and vice versa, In the phenomenon of disulfide exchange. disulirde bonds break and rclbrm in different positions. causing incorrect folding of the protein. Major changes in the three. dimensional structure of the peptide can abolish activity. Oxidation of the aromatic rings of His. Trp. and Tyr residues is believed to occur with a variety of oxidizing enzymes.

Physical Instability of Proteins" Chemical alterations are not the only source of protein instability. A protein is a large, globular polymer that exists in some specific forms of secondary. tertiary, and quatemary structure. A protein is not a fixed, rigid structure. The molecule is in dynamic motion, and the structure samples an array of three-dimensional space. During this motion. noncovalent intramolecular bonds can break, reform, and break again. but the overall shape remains centered around an energy minimum that represents the most likely (and pharmacologically active) confonner of the molecule. Any major change in the conformation can abolish the activity of the protein. Small drug molecules do not demonstrate this problem. A

globular protein normally folds so that the hydrophobic groups are directed to the inside and the hydrophilic groups are directed to the outside. This arrangement facilitates the water solubility of the protein. If the normal protein unfolds. it can refold to yield changes in hydrogen bonding, charge. and hydrophobic effects. The protein loses its globular structure, and the hydrophobic groups can be repositioned to the outside. The unfolded protein can subsequently undergo further physical interactions. The loss of the globular structure of a protein is referred to as de,ta:urwion.

Denaluration is, by far, the most widely studied aspect of protein instability. In the process, the three-dimensional folding of the native molecule is disrupted at the tertiary and, possibly. the secondary structure level. When a protein denatures, physical structure rather than chemical composition changes. The normally globular protein unfolds, exposing hydrophobic residues and abolishing the native threedimensional structure. Factors that affect the denaturation of proteins are temperature, pH. ionic strength of the medium. inclusion of organic solutes (urea. guanidine salts. acelamide. and forniamide). and the presence of organic solvents such as alcohols or acetone. Denaturation can be reversible or irreversible. If the denatured protein can regain its native form when the denaturant is removed by dialysis, reversible denaturation will occur. Denatured proteins are generally insoluble in water, lack biological activity, and become sus-

174

Wi/so,, and

TeAtbook

of Organic Medicinal and Phannaceutical chemistry

Hydrolysis-Deamldation 0

+

Mn 0

NH2 1:!

1L

NH3

Asp

0

NH2

NH3

+ Gin

NH2

Carbanion Intermediate Planar sp2 hybridized

o-Amlno

add

(aspartate): self-catalysis

If

I R\

C

8

Base-Catalyzed

Eiinination

X= a good leaving group (Cys, Set, Phe, Tyr, Lys)

b

Enolate Intermediate

Figure 6—11 . a. Protein sition reactions. b. B-Elimination.

Chapter 6 • lSio:ec/iiiologr and Drug I)israierv

hydrolysis. The air—water interface a hYdrophobic surface that can facilitate protein 'cluluratsin Interfaces like these are commonly encounin drug delivery devices and intravenous (IV) bags. Surface adsorption of proteins is characterized by adheto cn,.ylnatic

of the protein tO surfaces, such as the walls of the conol the dosage form and drug delivery devices. ampuls. asi IV tubing. Proteins can adhere to glass, plastics. rubber.

and polyvinylchloridc. This phenomenon is to as flueeularion, The internal surfaces of intrave— nsa delivery pumps and IV delivery bags pose particular of this kind. Flocculated proteins cannot be dosed

results when protein molecules, in aqueous stiwion, seIf'assocjate to form dinners, trimers. (etramers, and large macromolecular aggregates. SeIf-assoon the pH of the medium as well as solvent ionic strength, and dielectric properties. Mod amoutits of denaturants (below the concentration that %een'gsliml

saud cause denaturalion) may also cause protein aggrega-

Ian. Partially unfolded intermediates have a tendency to Coneetitrated protein solutions, such as an immunglohiilin for injection. may aggregate with storage time The presence of particulates in the preparation is phannacist's clue that the antibody solution is defective. Precipitation usuully occurs along with denaturation. De-

insesligiaions have been conducted with insulin. finely divided precipitate on the walls of an

hrch brats a

untu,Iuuut device or its dosage form container. It is believed that insulin undergoes denaturution at the air—water interIacc. lacilitatitig the precipitation process. The concentration I .'inc ion. pH, and the presence of adjuvants such as protanise ,ilso affect the precipitation reaction of insulin.

Immunogeulcity of Blotedrnologkally P,oduced Pnncins by their very nature are antigens. A humazi protein, at

its typical physiological concentration. may

cthihlt completely different immunogenic properties when administered in the higher concentration Ihat would be used a drug. Unless a biotechnology-derived protein is engiurered to be 10(1% conipleinentaiy to the human form, it sill differ among several major epitopes. The protein may Ii:use moditicutions of its amino acid sequence (substitutions

sue amino acid fur another). There may be ttdditions or Idetions of anhino acids. N-terminal methionyl groups, infolding patterns, or oxidation of a sulfurside chain of a methionine or a cysteine. Addi!slall, shrtt a protein has been produced by using a bactenjl vector, a finite amount of imrnunoreactive material may unto the final product. All of these listed items contribute lie .rntigcnicity of a biotechnologically produced protein. \Vlucn ii is adniinistercd to a human patient, the host's imi

muse

175

DELIVERY AND PHARMACOKINETICS OF BIOTECHNOLOGY PRODUCTS99 As with any drug class, the medicinal chemist and pharmacisc must be concerned with the absorption, distribution, me-

tabolism, and excretion (ADME) parameters of protein drugs. Biotechnology-produced drugs add complexities that are not encountered with "traditional" low-molecularweight drug molecules. ADME parameters arc necessary to compute pharmacokinetic and pharmacodynainic parameters for a given protein. As for any drug. these parameters

are essential in calculating the optimum dose for a given response. determining how often to administer the drug to obtain a steady state, and adjusting the dose to obtain the best possible residence time at the receptor (phammacodynamic parameters).

Delivery of drugs with the molecular weights and properties of proteins into the human body is a complex task. The oral route cannot be used with a protein because the acidity of the stomach will catalyze its hydrolysis unless the drug is enieric coated. Peptide bonds are chemically labile, and proceolylic enzymes that are present throughottt the body can

attack and destroy protein drugs. Hydrolysis and pcptidase decomposition also occur during membrane transport through the vascular endothelium. at the site of administration, and at sites of reaction in the liver, blood, kidneys, and most tissues and fluids of the body. It is possible to circumvent these enzymes by saturating them with high concentra(ions of drug or by coadministering peptidase inhibitors. Oxidative metabolism of aromatic rings and sulfur oxidation can also occur. Proteins typically decompose into small fragments that are readily hydrolyzed. and the individual amino acids are assimilated into new peplidcs. A potentially serious hindrance to a pharmacokinetic profile is the tendency of proteins administered ax drugs to bind to plasma proteins such as serum albumin. If this happens, they enter a new biodistribution compartment from which they may slowly exit. Presently, the roulcs of administration that are available for protein drugs are largely subcutaneous and itnramuscular. Much ongoing research is targeted at making peptide drugs more bioavailable. An example of this is conjugation of interleukin-2 with polyethylene glycol (PEG). These socalled pegylated proteins tend to have a slower elimination clearance and a longer 1, than inierleukin-2 alone. Another strategy being used is the installation of a prosthetic sugar moiety onto the peptide. The sugar moiety will adjust the

partition coefficient of the drug, probably making it more water soluble.

RECOMBINANT DRUG PRODUCTS

will react to the protein just as it would to a

attack and neutralize it. This is why research has undertaken to create 100% human protein drugs, such m usulin. which patients will need to take for a long time. In .iddition. some of the most promising biotechnology prodhe monoclonal antibodies, are produced in mice by use u lucu:uni:ed genes to avoid human reaction to the mouse

Human Insulin. Recombinant, 100102 Human insulin was the first pharmacologically active biological macrotnolecule to be produced through genetic engineering. The FDA approved the drug in 1982 for the treatment of type I (insulindependent) diabetes (see Chapter 25). The insulin protein is a two-chain polypeptide containing SI amino acid residues. Chain A is composed of 21 amino acids, and chain B con-

176

II'iIson and Gi.c void's Textbook of

Medicinal and Phamiaceuticai Chemistry

tains 30. The human insulin molecule has three disulfide linkages. CysA7 to CysB7. CysA29 to CysB19, and an intrachain linkage. to CysA11. Insulin is secreted by the 46-cells of the pancreatic islets of Langerhans, initially as a single peptide chain called proinsulin. Enzymatic cleavage of the propeptide releases the insulin. Historically, insulin was isolated from bovine or porcine

terminus of the B chain. Insulin glargine. administered subcutaneously (SC), has a duration of action of 24 to 48 hours. The alteration in basicity of this agent causes it to precipitate at neutral pH, creating a depot effect. Insulin rDNA has been very successful. The only problem has arisen in patients who have been using porcine or bovine insulin for a long time. Some patients who are switched to

sources. Using these agents was not without difficulty. Both porcine and bovine insulin differ in amino acid sequence.

rDNA human insulin report difficulty in "feeling their glucose level," and these patients require extra counseling in

with Ala replacing Thr at the C terminus of the human B Bovine insulin also differs in sequence from human insulin, with Ala substituting for Thr at A8 and Val

the use of the recombinant hormone.

chain

substituting for isoleucine at A10. These differences, small though they may seem, result in immunological reactions in some patients. Adjustments to the formulation of bovine and porcine insulin led to products that differed in time of onset, time to peak reduction in glucose, and duration of action. These parameters were varied by addition of pronamine and zinc (which yielded a particulate insulin with a longer duration of action). and adjustment of the pH to neutrality, which stabilized the preparation. Insulins were characterized as reg-

ular (short-duration llctin. 4 to 12 hours). semilente (ultrashort duration). lente (intermediate II to 3 hours to peak. 24 hours durationi), and ultralente (extended duration). An o(

NPhI (,neutvat pcotamine

Hagedorn). which had an intermediate time of onset and time to peak (ito 3 and a tong duration of action (16 to 24 hours).

Producing a recombinant insulin that is chemically and physically indistinguishable from the human pancreatic hormone was a major accomplishment. The problem with immunoreactivity has been eliminated, the pyrogen content of the rDNA product is nil, the insulin is not contaminated with other peptides. and the hormone can be biosynthesized in larger quantities. Human insulin (rDNA) is available as Humulin, Novolin, and a number of analogues that differ in

their phamiacokinetic profiles. Humulin is produced by using recombinant E. cvii: Novolin is prepared by using recombinant S. cerevixiae. a yeast. There have been modifications in the production procedure since the initial success-

Glucagon.'°4

The hormone glucagon (GlucaGen) is

biosynthesized in the pancreas as a high-molecular-weight protein from which the active macromolecule is released by proteolytic cleavage. Glucagon is a single chain of 29 amino acids and generally opposes the actions of insulin. Bovine and porcine glucagons. which possess structures identical with human glucagon, have been in use for years. The rDNA form has been approved by the FDA for use in severe hypo glycemia and as a radiological diagnostic aid. Glucagon relaxes smooth muscles in the gastrointestinal (GI) tract. dc creasing GI motility and improving the quality of radiological examinations. In the treatment of severe hype glycemia in insulin-dependent diabetics, GlucaGen causo to co5wett to untreated. vere hypoglycemia (low-blood-sugar reactions) can prolonged loss of consciousness and may be fatal. The rDN\

drug has the benefit that there is no chance of bovine spongiform encephalopathy from glucagon therapy This condition, also known as mad cow disease, is causedt a prion that was suspected to infect animal pancreas tissa

Human

Growth

Hormone,

Human growth hormone (hGH) is a protein that is for normal growth and development in humans. hUH many aspects of human development and metabolism eluding longitudinal growth, regulation (increase) of pmtcr synthesis and lipotysis. and regulation (decrease) of metabolism. hUH has been used as a drug since the l95b

ful biosynthesis. Prior to 1986, Humulin was produced by creating two different vectors, one for the A chain and one for the B chain, and inserting them into E. coli. The A chain

and it has been extremely successful in the treatment olck

and the B chain would be secreted into the medium, and the

Willi syndrome. In its long history the hormone has ('cc remarkably successful and free of side effects. The primary form of hUH in the circulation is a 22.kth nonglycosylated protein produced in the anterior pituiur

two were joined chemically to form rDNA insulin. Today, the entire proinsulin gene is used to create a recombinant organism. and the connecting peptide in proinsulin is cleaved by two enzymes (an endopeptidase and a carboxypeptidase

B). yielding insulin (for details see Chapter 25). Insulin rDNA is available in severaO°3 forms. Insulin lispro (Hurnalog) has a more rapid (15 to 30 minutes) onset and a shorter duration (3 to 6.5 hours) of action than regular

human insulin (onset 30 to 60 minutes, duration 6 to tO hours). It is effective when administered 15 minutes before

a meal, unlike regular insulin, which must be injected 30 minutes before a meal. In lispro, the B-chain amino acids and B2.,Lys are exchanged. Insulin aspart (Novolog), onset IS to 30 minutes. duration 3 to 6.5 hours, with a single

amino acid substitution of Asp for Pro at B28, is effective when administered 5 to 10 minutes before a meal. The ultra-

long-acting agent insulin glargine has the Asp at A21 replaced by Gly and has two Arg residues added at the C

sic growth hormone deficiency, chronic renal in women. and Pradc

and cotnposed of 191 amino acid residues linked by bridges in two peptide loops. The structure of hUH is

lar, with four antiparallel a-helical regions. Endogenci. hGH is composed of about 85% of the 22-Wa mononict.' to 10% of a 20-kDa monomer, and 5% of a mixture of tide-linked dimers. oligomers. and other modified fonri. From the late 1950s, hUH was isolated from pituilany c tracts of cadavers, A prion associated with the was suspected to cause Creutzfeldt-Jakob disease, a degenerative neurological disorder. The first use of recombinant hGH (rhGH) was repslz. in 1982. rhGH preparations were first produced in £ c These preparations contained a terminal methionine and" amino acids. Natural sequence rhGH has since beet duced in mammalian (mouse) cell culture.

Chapter 6 • Biotechnology and Drug Discovery

n

Somauern, the first recombinant preparation, introduced 985. containc the natural 191-amino acid primary Se-

4UCOCC plus one methionyl residue on the N-terminal end. The sonrairtipin products all contain the 191-amino acid se-

177

tissue to stimulate iodine uptake into the gland, organification of iodine, and secretion of thyroglobulin. Ta. and T4. The drug is used as a tool for radioiodine imaging in the diagnosis of thyroid cancer.

qucnce and are identical with the ItCH produced by the pitui-

lam gland. The three-dimensional crystal structure shows the protein is oblate. with most of its nonpolar amino aid side chains projecting toward the interior of the molecide. This rhGH is pharmacologically identical with natural hGH.

Most current formulations of

rhGH are supplied in lyophi-

wed form and must be reconstituted prior to injection. Typi-

cally, 5 to 10 mg of protein are supplied in a powdered and/or mannitol phosphate buffer. The prepardtion

Cytokines HEMATOPOIETIC GROWTH FACTORS

Among all of the events taking place in the immune system. the bone marrow, and the bloodstream, the process of hematopoiesis is probably the most complicated. All of the cells in the blood and the immune system can trace their lineage back to a common, parental hematopoietic stem cell in the bone marrow. This cell is referred to as pluripoten: because

sill remain stable for 2 years.

under the proper stimulation it can differentiate into any other cell. The proce.sses of maturation, proliferation, and differentiation are under the strict control of a number of

niGH undergoes rapid, predictable metabolism in vivo in the kidney and the liver. Chemically, the metabolites are

cytokines (Table 6-5) that regulate a host of cellular events. Two distinct blood cell lineages exist: the lymphoid lineage

those expected for any peptide: deamidation of Asn and GIn and oxidation of Met, Tm, His, and Tyr.

that gives rise to B and T lymphocytes, and the myeloid

reconstituted with sterile water for injection, and the stabiliyof the product is quite good. If stored at 2 to 8°C, rhGH

lineage that produces granulocytes (macrophages. neutro-

phils, cosinophils, basophils, and mast cells), as well as The gonadolroFsaIIkle.Stimulating Hormone.'°''°8 pin Iollicle-stimulating hormones (FSH), follitropin alfa iGunal-FI and follitropin beta (Follistim). are produced in he anterior lobe of the pituitary gland. FSH can function in ISO ways. On the one hand, it causes increased spermatogen-

esis in males. On the other hand, in concert with estrogen and luleiniring hormone, it stimulates follicular growth and deselopment in females. Consequently, FSH may be useful in he lieatnnent of infertility. FSH is a member of a superfamily of proteins, all structur:llv related. which includes luteinizing hormone (LH), chorimc gonadoiropin, and thyroid-stimulating hormone (TSH).

platelets and erythrocytes. As many as 20 of the hematopoicsis-associated cytokines have been cloned and expressed. Some of these are listed in Table 6-5.

The cascade is shown in Figure 6-12. A further feature of the pluripolent stem cell deserves mention. Each stem cell divides into two daughter cells, one an active hematopoietic progenitor and one quiescent. The active precursor matures to give hematopoietic progenitors and then circulating blood

cells. The quiescent stem cells rejoin the stem cell pool. Hence, the number of parental cells is always the same. This process is termed self-renewal.

It is a heterodimer, the a subunit contains 92 amino acids.

PRODUCTS

and the /3 subunit contains ill amino acids. The protein

Erythropoietin Alfa.1"

rather heavily glycosylated and has a molecular mass of approximately 35 kDa. The traditional source for isolation was postmenopausal urine, which provided a preparation that was less than 5% pure and was significantly conaminaled by LH. The recombinant human FSH (rhFSH) is 'induced in a mammalian cell line, the CHO. are the same protein, but Follitropin a and follitropin hey differ with respect to the way they are formulated. Both

combinant Epoetin Alfa, Epogcn, Procrit, is a glycoprotein that stimulates red blood cell production. It is produced in

113

Eiythropoietin alfa. re-

TABLE 6-5 Cytoklnes Th at Have Been Cloned Cytokina

BiologIcal Function

a form is formulated with ucrose (as a bulk modifying agent and a lyoprotectant) and form contains ihr components of phosphate buffer. The ucnn'se. with sodium citrate as a stabilizer and polysorbate

lnterlcukin-3

Multi-stem cell factor-, controls branching from niyeloid stem ucil

as a lyoprotectant and a dispersant. The products are :aconsnituted immediately before administration. The shelf of both preparations is 2 years when they are stored in he stpplied containers at less than 30°C (not frozen) and

Intcrleukln-4

Switches B cctls from IgO to IgE

lntcrleukin-5

Activates cosinophik

lnterteukins-6 and '1

Differentiation arT lymphocytes

rrnerleukln.I2

Controls the ratio of T,11 toT112

rrulected from light.

Erythropoletin

Stimulates rest cell production

Granulocyte-macruphago

Acts with lL-3 to control myeluid

Thytotropin Alpha.'°'"°

Human thyroid-stimulating

hormone (TSH). thyrotropin alpha (Thyrogen). is a heterodascric protein of molecular mass —28,000 to 30,000 Da. The a subunit is composed of 92 amino acids, and the ubriniL 112. The specificity of the protein is controlled by he $subunil. TSH binds to TSH receptors on normal thyroid

cells or on well-differentiated cancerous thyroid

colony-stimulating factor

branch

Gr.rnulocytc colony-stimulating foctor

Neutrophil production

Macrophage cuiony.srinruiating factor

Macrophage production

Stem cell factor

Coonrots activity through myelold branch

178

tVilwn and

Medicinal and Pharnwceurieol chemistry

textbook ',f

QuIescent Daughter Cell

Plurlpotent Stem Cell SCF IL-3 OM-CSF EPO

IL-3 GM-CSF EPO

Myelold Stem Cell

Lymphold Stem Cell

SCF IL-3 GM-CSF EPO

I

SCF IL-3 GM'CSF

I I

SCF IL-3

I

4, I

/\ ® ®®® I

GM-CSF IL-3

IL-3 GM-CSF

I

$ EPO

!

GM-CSF I M-CSF I

EPO

I

IL-2 lL-6

IL-3

IL-i

GM-CSF IL-3

!1L4

I

4,

Erythcocytea

Platolol.

Neutroptilts

EOSInOpIrIIe

Basoplilte

B Lyniptiocytea

T Lymphocytes

Figure 6—12 • Cytokine-mediated cascade leading to different blood cell types. EPO. erythropotetin; GCSF. granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL-X interleukins; M-CSF, macrophage colony-stimulating factor; SCF, stern cell factor; TPO, thrombopoietin.

the proliferation and differentialhe kidney, and it tion of specially committed erythroid progenitors in the bone marrow. Epoetin alfa (Epogen) is a 165-amino acid glycoprotein that is manufactured in mammalian cells by rDNA technology. The protein is heavily glycosylated and has a molecular mass of approximately 30,400 Da. Erythropoictin is composed of four untiparallel a helices. The rDNA protein has the same amino acid sequence as natural erythropoietin. Epoetin is indicated to treat anemia of chronic renal failure

patients, anemia in ,idovudine-treated HEY-infected patients. and in cancer patients taking chemotherapy. The results in these cases have been most patients respond with a clinically significant increase in hematocrit.

tion of granulocytes (especially neutrophils) by hematopoietic stem cells in the bone marrow. G-CSF is a glycoprotein produced by monocytes, blasts, and endothelial cells. G-CSF is a protein of 174 a molecular mass of approximately 18.800 1

The native protein is glycosylated. Filgrastim selectively stimulates proliferation and diffe entiation of neutrophil precursors in the bone marrow. flL leads to the release of mature neutrophils into the from the bone marrow. Fi Igrastim also affects mature nests phils by enhancing phagocytic activity, priming the metabolic pathways associated with the respiratory enhancing antibody-dependent killing, and increasing f:

Filgrastim.IM ItS

expression of some functions associated with cell

ulating

antigens.

Filgra.stim. granulocyte colony-stim(G-CSF). Neupogen, stimulates the prolifera-

Chapter 6 • Biotechnology and Drug Discovery

In patients receiving chemotherapy with drugs such as

179

Viius

doxorubicin. and etoposide, the mciot Itcutropenia accompanied by lever is rather high. Administration of G-CSF reduces the time of neutrophil reand duration of lever in adults with acute myelogenuns kukemia. The number of infcctions, days that antibiot-

ire required, and duration of hospitalization are also Natural Killer

reduced.

is identical with G-CSF in its amino acid scqseiwe. except that it contains an N-terminal methionine hat is necessaiy for expression of the vector in E. cpu. The protein is not glycosylated. Filgrastim is supplied in a 0.01 N sodium acetate buffer containing 5% sorbitol and 0.004% 80. It should be stored at 2 to 8°C without freez-

Infectod Host Cell

Cell

FIgure 6—13 • Antiviral mechanism of action of the inter. ferons.

Becaplermin is produced by a recombinant strain of S. cere-

Under these conditions, the shelf life is 24 months. Avoid shaking when reconstituting; although the foaming will not harm the product, it may alter the amount of drug

visiae containing the gene for the B chain of PDGF. The protein has a molecular mass of approximately 25 kDa and is a homodimer composed of two identical polypeptide

that is drawn into a syringe.

chains that are linked by disulfide bonds. It is a growth factor that activates cell proliferation, differentiation, and function, and it is released from cells involved in the healing process. Becaplermin is formulated as a gel recommended for topical use in the treatment of ulcerations of the skin secondary to diabetes.

U8 Sargramostim. granulocytemn.wniphage colony-stimulating factor (GM-CSF). Leukine.

is a glycoprolein of 127 amino acids, consisting of three molecular subunits of 19,500, 16,8(X). and 15.500 Do. The

endopenous lomi of GM-CSF is produced by T lymphotes, endothelial tibroblasts. and macrophages. Recombirout GM.CSF. produced inS. cerem'i.ciae. differs from native

human GM-CSF only by substitution of a leucine for an

The intcrfcrons arc a family of small proteins or glycoproteins of molecular masses ranging from 15,000 to 25,000

arginine at position 23. This substitution facilitates expres-

Da and 145 to 166 amino acids long. Eukaryotie cells secrete

ol the gene in the yeast. The site of glycosylation in he recombinant molecule may possibly differ from that of the native protein.

interferons in response to viral infection. Their mechanism of action is bimodal. The immediate effect is the recruitment of natural killer (NK) cells to kill the host cell harboring the

Sargramostinr binds to specific receptors on target cells and induces proliferation, activation, and maturation. Ad-

virus (Fig. 6-13). Interferons then induce a state of viral resistance in cells in the immediate vicinity, preventing

ministration to patients causes a dose-related increase in the

spread of the virus. Additionally. interferons induce a cascade of antiviral proteins from the target cell, one of which

white blood cell count. Unlike G-CSF. GM-CSF is a muhilineage hematopoietic growth factor that induces partially committed progenitor cells to proliferate and differenhiale along thin granulocyte and the macrophage pathways.

Ii also enhances the function of mature granulocytes and GM-CSF increases the chemotactiC. antifungal, and antiparasitic activities of granulocytes and ntonmsytes. It also increases the cytotoxicity of monotoward neoplastic cell lines and activates polymorpholeukocytes to inhibit the growth of tumor cells. Sargmmoslim is used to reconstitute the myeloid tissue alter aulologous bone marrow transplant and following in acute myelogenous leukemia. The prepara-

is 2',5'-oligoadenylate synthetase. This enzyme catalyzes the conversion of ATP into 2',S'-oligoadenylate, which activates ribonuclease R. hydrolyzing viral RNA. Interferons can be delined as cytokines that mediate antiviral. antiproliferative, and immunomodulatory activities. Three classes of interferon (IFN) have been characterized: a (alpha), /3 (beta), and y(gamma) (see Table 6-6). a-Interferons are glycoproteins derived from human leukocytes. /3Interferons are glycoproteins derived from fibroblasts and macrophages. They share a receptor with a-interferons. yInterferons are glycoprotcins derived from human T lympho-

inn decreases the incidence of infection, decreases the numher of days that antibiotics are required, and decreases the durjtimiu of hospital stays.

Sargr.mmostini is supplied as a solution or powder (for solutioni. Iloth forms should be stored at 2 to 8°C without mrwing. The liquid and powder have expiration dates of 24 months. Thc reconstituted lx)wder and the aqueous solution 'hould not be sha en.

TABLE 6—6

Interferon Type Alphu

lnterferons Used TherapeutIcally Endogenous Source

AvaIlable Drug Products

Lcukocytcs

ulfa-2a

Interferon utfa-2b

Becaple,min.'T' Becaplermin. Regranex Gel, an endmmgctmoas ptmlypeptide that is released from cells that are inmolsed in the healing is a recombinant human

plaleki-slerised growth factor (r-hPDGF-BB). The "BB" that hecaplermin is the hoinodimer of the B chain.

aifa-2c ttcta

Eihmhtasts, mucrophages

tllema'lim

Gainnia

TLymnphocyrcu. nuturul

Gamma-lb

lb kilter cells

180

Medicinal and Pliarnraceuiica! Ciu',njOrv

Wilson am! Girt',,iml 's Textbook of

TABLE 6—7

Summary of the x-lnterferons Interferon

Interferon

AIfa-2a

AIfa-2b

Interferon Alfa-ni

Interferon Alfa.n3

Interferon Alfacon-1

Tr.uic nwne

Roteron A

Iiitnsn A

wdtrcroit

Aileron N

Dosage form

Solution. powder

Solution, powder

Solution

Solution

Solution

Soisent

Sodium chloride. excipients

Buttered saline

ISuflered saline

Ruflered saline

phosptiate-bulfered saline

indications

Hairy cell leukemia, AIDS-rekited

hairy cell lcukeniia. AIDS-related Kuposi's sarcinna, condytonrura

Chronic hepatitis C

Condylomnia ucuminata

Chronic hepatitis C'

SC or IM

huitr.ilesionaI

SC

Human lyinphobt.tstoid

Human leuk*icytcs

E. coil

Kaposi's sarcoma. chronic hCpatiiis C Rouleir'

SC. lM. IV, infusiciri or

Siinrcc

F rob

acunuinuta, chronic hepatitis B. chronic hcpatitis C

SC. IM. IV, infusion or intrulecional iou

cell line St. oat.cuiuncou.Iv: 154.

tV. mnmr.wcnousls

cytes and NK cells. These interterons are acid labile and used to be called 'type 2 interferon." The rcceptor fir IFNy is smaller than that fir IFN-a and 90 to 95 kDa versus 95 to I 10 kDa. respectively. The three classes are not homogeneous. and each may contain several different

cells. Modulation of the host ituniune response probably plays tt role in the antitumor activity of interferon alfu-2a. The interferon is supplied as a solution or as a powder

molecular species. For example. at least 18 genetically and molecularly distinct human a-interferons have been identilied, each differing in the amino acid substitution at positions alfa-2b. and alfa-2c have been 23 and 34. lntertCrons purified and are either in clinical use or in development. A

0.33% phenol. The interlCron vials, if properly stored at 2 Ia 8°C without freezing. expire in 30 months. Prefilled syringes

listing of commercially available a-inccrferons is given in

Pegylated Interferon AIfa-2a.2'

Table 6-7. As a class, the interferons possess some common side effects. These arc lb-like symptoms, headache, fever, nutsdc aches, back pain, chills, nausea and vomiting, and diarthea. At the injection site, pain, edema, hemorrhage, and inflammation are common. Di,ziness is also commonly reported.

For the pharmacist. when predicting drug interactions with the interferomts. eytochrome P-450 metabolism should always be a key consideration. Most of the interferotis itihibit cytochrome P-450. causing drugs that are nietaboli,ed by

this route to reach higher-than-nonnal and, possibly. toxic concentrations in the blood and tissues.

for solution. The solution contains

NaCI. The powder

contains 0,9% NaCI. 0.17% human serutu ttlhuniin. and

expire itt 24 nionths. The solutions should not be shaken because the albumin will cause frothing. Pegylated interferon

alfa-2a. Pegasys. is a covaletit conjugate of recombittant terferon all'a-2a (approximate molecular mass. 20 kDa) ssilh

singly-branched bis-monomethoxypolycthylene glycal (PEG) chain (approximate molecular mass. 40 kDa). The PEG tnoiety is linked at a single site to the interferon alfa moiety by a stable antide botid to lysine. Peginterferon alfaa

2a has an approximate molecular mass of 6() kDa. Pcgasys provides sustained therapeutic serum levels for up to a fuH week (168 hours). The drug is approved for the treatment of adults with chronic hepatitis C who have compensated liver disease and who have not been previously treated wilh interferon alfa. Efficacy has also heemi demonstrated in pa tients with compensated cirrhosis.

PRODUCTS: a-INTERFERONS

Interferon AIfa-2b (Recombinant).'22

Interferon AIfa-2a (Recombinant).'20

alfa-2b. Intron A. a water-soluble protein of 165 amino acids

Interferon aI fa2a (recombinant). Roferon A. is expressed in an E. co/i sys-

tent attd purified by using high-affinity mOUSe monoclonal antibody chromatography. The protein consists of 165 amino acids with a molecular mass of approximately 19.0(X) Da. and contains lysine at position 23 and histidine at position

Interferon

and an approximate molecular mass of 19.200 Da. is cx pressed from a recombinant strain of E. coil. This interferon molecule possesses ati arginine at position 23 and a histidine

ttt position 34. Interferon alfa-2b is a broad-spectntm agent. It is mdi. cated for hairy cell leukemia. condylomna acurninata (genital

34.

is used in the treatment of hairy cell leukemia and AIDS-related Kaposi's sarconta in selected

or venereal warts). AIDS-related Kaposi's sarcoma, and chronic hepatitis B and C infections.

patients over 18 years of age. It is also used to treat chronic hepatitis C. and in patients with this disease. interferoti alfa2a can nomialiie seruni alanine antinotransierase (ALT) lev-

by infusion or by intralesional mutes. The dose is I to 35 million IU/day. depending on the application. The drug

Interferon

els. improve liver histology, and decrease viral load. The drug has a direct antiproliferative activity against tumor

Intron A can be administered by the SC. lM. or IV router.

supplied as a solution or as a powder for solutioti. attd boTh

forms contain albumin. glycine. and sodium phosphate

Chapter 6 a 'tiller. Hence, they should not be shaken. Vials of solution stiuld he stored at 2 to 8°C without freezing. The powder 'stable tar 18 months at room temperature or 7 days at

Interferon Alfa-nl.'23 interferon alfa-n I. Wellferon, uhisture of o-interfcrons isolated from a human lymphshiastoid cell line alier induction with mouse parainlluenza

Scndai strain). Each of' the subtypes of IFN-a in this product consists of 165 or 166 amino acids with an iype I

ture

molecular rna.cs of 26,000 Da. The product is a mixif each of the nine predominant subtypes of alfa-n I

in

is indicated to treat chronic hepatitis C

1$ years of age or older who have no decompenliver disease. The exact mechanism of action for inter-

alla-ul in the treatment of this disease has not been

and 1)rug Discovers

181

and assigning the tHus! COflflflOfl amino acid to each variable

position. Additionally, four amino acid changes were made to facilitate synthe.sis. The DNA sequence is also constructed

by chemical synthesis. Interferon alfacon-l differs from interferon alia-n2 at 20/166 amino acids, yielding 88% homology. The protein has a molcetilar mass of approximately 19.400 Da.

Interferon ulfacon- I is used in the treatment of chronic hepatitis C virus infection in patients 18 years of age or older

with compensated liver disease and who have anti-HCV serum antibodies or HCV RNA. The drug is administered by the subcutaneous route in a dose of 9 3 times per week, Interferon alfacon- I is supplied as 'a solution in Ishosphale-buffered saline. It should

be stored at 2 to 8°C without freezing. Avoid shaking the solution.

dacidareiL

This drag may be administered SC or EM. with a usual disc ot 3 million Hi 3 times per week. Interferon alfa-n I is 'uppllL'd as a solution containing tromethamine and buffered sline with human albumin as a stabilizer. Hence, the soluon should nor be shaken. The solution should be stored at 1n5C without freezing, and should be discarded if freezing

Properly stored solution expires in 24 months. Interferon AIfa-n3'24 Interferon alfa-n3. Aileron N. expressed from human leukocyres that are with avian Sendai virus. The Sendai virus propagated in chicken eggs. The protein consists of at least 14 molecular subtypes. The average chain length is amino acids, and molecular mass range is 16.000 to 17.1881 l)a. The polydisperse interferon alfa-n3 is extremely pare because it is processed by affinity chromatography over :i bed 01° mouse monoclonal antibodies specifically raised hit the protein.

Interferon alfu-n3 is indicated for intralesional treatment of reuractorv or recurrent condylonna acunhinata (genital tons I in patients 18 years of age or older. These xvafls are

PRODUCTS: 13-INTERFERONS

A listing of two commercially available

is given in

Table 6-8.

Beta-la (Recombinant).'2' Interferon beta-la (recombinant). Avonex. is a glycoprotein with 166 amino acids. It has a molecular mass of approximately 22.000 Da. The site of glycosylation is at the asparagine Interferon

residue at position 80. Interferon beta. I a possesses a cysteinc residue at position 17. as does the native molecule. Natural IFN-fl and interferon bela-lu are glycosylated. with each

containing a single carbohydrate moiety. The overall complex has 89% protein and II carbohydrate by weight. Recombinant interferon beta-I a is expressed in CHO cells con-

taining the recombinant gene br human IFN-/3 and is equivalent to the human fonu secreted by fibrohlasts. Interferon beta-Ia is indicated for the treatment of relapsing lbmss of multiple sclerosis. Patients treated with interferon beta-I a demonstrate a slower progression to disability and a less noticeable breakdown of the blood—brain harrier

with human papilloma virus (HPV). Interferon is especially useful in patients who haven't responded well Its other modalities (podophyllin resin. surgery. •ihla.u3

Interferon alfa-n3 is also being inves-

for the treatment of non-Hodgkin's lymphoma, herpes simplex. rhinovirus. vuccinia. and varicella zoster. A usual dose in condyloma acuminata is 250.000 lU/wart. with a 31)-gauge needle around the base of the Ic"in Interkran alfa'n3 is contraindicated in persons sensitive ho mouse immunoglobulin G. egg protein, and neomycin. .supplied as a solution with the protein Interferon alftu-n3 ii phuaphate-huffered saline with phenol as a preservative. list solution should be stored at 2 to 8°C without freezing. Properly stored solution expires at IS months.

Interferon Alfacon-1 (Recombinant). interferon alfarecombinatit). Infergen.'2° is a "consensus'' intershares structural elements of IFN—a and several 'ubtypes. The range of activity is about the same as the other ilpli.u species, but the specific activity is greater. The 166.amino acid sequence of alfacon- I is synthetic. It i.usdeseloped by comparing several natural IFN-a subtypes

TABLE 6-8

3-lnterferons Interferon Beta-la (Avonex)

Interferon Beta-lb (Betaseron)

Recombi,iani

Cl-tO cetis

Fc'hrs-ic/,iu you

Type

Maw eomplcx

NisI glycosytsied

carbohydrate

or 6 million lU/mi.

Coni,cnlraiion

31)

251) p.g or 11 uttitlion

Supplied form

Powder for rcconstituIion

Powder for rcconslituuiiu)n

Oittjcun

Sterile water—no preservative'.

NaCI 0.54% without prscrs'ativcs

Storage

2—SI

I)osage

31)

Route

tnuraunuseutar

Suticutaucous

Notable aide

In3eciion site rsac'tuiuns.

Injection site rcactioas.

cffccls

do not Irecec once a week

3%: no necrosis

lU/niL

2—S Ct do not freeze 25(1

every other day

necrosi'..

18.2

Wilson and (3isvolds Textbook of Organic Medicinal and Pharmaceutical Chemi.ctrv

as observed in gadolinium-enhanced magnetic resonance imaging (MRI).

Although the exact mechanism of action of interferon beta-la in multiple sclerosis has not been elucidated, it is known that the drug exerts its biological effects by binding to specific receptors on the surface of human cells. This binding initiates a cascade of intracellular events that lead to the expression of interferon-induced gene products. These microglobuinclude 2',5'-oligoadenylate synthetase and lin. These products have been measured in the serum and

in cellular fractions of blood collected from patients treated with interferon beta-la. The functionally specific interferoninduced proteins have not been defined for multiple sclerosis.

Adverse effects include a flu-like syndrome at the start of therapy that decreases in severity as treatment progresses. Interferon beta-la is a potential abortifacient and an inhibitor

of cytochrome P450. The dosage form is a powder for solution that is reconstituted in sterile water. Excipienis are human albumin, sodium chloride, and phosphate buffer. The solution can be stored at 2 to 8°C and should be discarded if it freezes. The lyophilized powder expires in 15 months. After reconstitution, the solution should be used within 6 hours. The solution should not be shaken because of the albumin content.

Interferon

Interferon Beta- lb (Recombinant).'27 beta-lb. Betaseron. is a protein that is expressed in a recom-

binant E. coil. It is equivalent in type to the interferon that is expressed by human fibroblasts. Interferon beta-lb possesses 165 amino acids and has an approximate molecular mass of 18.5 kDa. The native form has 166 amino acids and weighs 23 kDa. interferon beta-lb contains a serine residue

at position Il rather than the cysceine in native IFN-fl and does not contain the complex carbohydrate side chains found

in the natural molecule. In addition to its antiviral activity, interferon beta-lb possesses immunomodulating activity. Interferon beta- lb is administered SC to decrease the frequency of clinical exacerbation in ambulatory patients with relapsing—remitting multiple sclerosis (RRMS). RRMS is characterized by unpredictable attacks resulting in neurological deficits, separated by variable periods of remission. Although it is not possible to delineate the mechanisms

by which interferon beta-lb exerts its activity in MS. it is known that the interferon binds to specific receptors on cell surfaces and induces the expression of a number of interferon-induced gene products, such as 2',S'-oligoadenylate synthetase and protein kinase. Additionally, interferon beta-

lb blocks the synthesis of INF-y, which is believed to be involved in MS attacks. Interferon beta-lb is supplied as powder for solution with albumin and/or dextrose as excipients. Ii should be stored at 2 to 8°C without freezing. After reconstitution the solution can be stored in the refrigerator for 3 hours. The solution should not be shaken.

A major difference between interferon beta-la and betalb is that beta-lb causes more hemorrhage and necrosis at the injection site than does interferon beta-I a. PRODUCTS: y'INTERFERON

Interferon Gamma-lb (Recombinant).128

Interferon gamma- lb. Actimmune. is a recombinant protein expressed

in E. coil. IFN-y is the cytokine that is secreted by human T lymphocytes and NK cells. It is a single-chain glycoprotcin composed of 140 amino acids. The crystal structure of the protein reveals several helical segments arranged to approximate a tone shape.

Interferon gamma-lb is indicated for reducing the frequency and severity of serious infections associated with chronic granulomatous disease, an inherited disorder charac-

terized by deficient phagocyte oxidase activity. In this disease, macrophages try to respond to invading organisms but lack the key oxidative enzymes to dispose of them. To coin-

pensate. additional macrophagcs are recruited into the infected region and form a granulomatous structure around the site. IFN-ycan stimulate the oxidative burst in macrophages and may reverse the situation.

Interferon gamma-lb is supplied as a solution in sterile water for injection. The solution must be stored at 2 to 8°C. without freezing. The product cannot tolerate more than 12 hours at room temperature.

THE INTERLEUKINS Aldesleukin.'29 Aldesleukin. T-cell growth factor, thymocyte-stimulating factor. Proleukin. is recombinant in an engineered strain of E. coil containing an analogue of the human IL-2 gene. The

recombinant product is a highly purified protein of 133 amino acids with an approximate molecular mass of 15,300 Da. Unlike native IL-2, aldesleukin is not glycosylated. has no N-terminal alanine. and has serine substituted for Cys at site 125. Aldesleukin exists in solution as biologically active. non-covalently bound microaggregates with an average size of 27 IL-2 molecules. This contrasts with traditional solution aggregates of proteins, which often form irreversibly bound structures that are biologically inactive. Aldesleukin enhances lymphocyte mitogenesis and stimu• lates long-term growth of human lL-2-dependent cell lines. IL-2 also enhances the cytotoxicity of lymphocytes. Indac. non of NK cell and lymphocyte-activated killer (LAK) cell activity occurs, as does induction of production. In mouse and human tumor cell lines, aldesleukin activates cellular immunity in patients with profound Iymphocytosis, eosino. philia. and thrombocytopenia. Aldesleukin also activates die

production of cytokines. including tumor necrosis factor (TNF). IL-I,and IFN-y. In vivo experiments in mouse tumor models have shown inhibition of tumor growth. The media. nism of the antitumor effect of alde.sleukin is unknown. Aldesleukin is indicated for the treatment of metastalic

renal cell carcinoma in adults, It is also indicated for the treatment of metastatic melanoma in adults. Research is under way on the use of aldesleukin for the treatment of various cancers (including head and neck cancers), treatment of acute myelogenous leukemia, and adjunct therapy in the

treatment of Kaposi's sarcoma. Renal and hepatic function is typically impaired during therapy with aldesleukin, so interaction with other drugs that undergo elimination by these organs is possible. Aldesleukin is supplied as a powder for solution. After reconstitution, the solution should not be shaken. The prepa. ration is solubilized with sodium dodecyl sulfate in a phos.

Chapter 6 • l!wtec-Ii,uiloç'v mu! Drug Discovery phate buffer. Aldesleukin should be stored as nonreconstituted ;xlwder at 2 to 8°C and never frozen. Reconstituted vials

he lroocn and thawed once in 7 days without loss of .wiivitv. It expires over a period of 18 months.

Denileukin Diftitox (Recombinant.'3°

Denileukin recombinant. Ontak. is an example of a drug that

acts like a Trojan horse. One part of the molecule is involved UI recognition and binds selectively with the diseased cell.

and a highly toxic second part of the molecule effects a kill. Denileukin diltitox is a fusion protein expressed by a reconihinant str.nn of h. roll. It is a rDNA-derivcd cytotoxic protein composed of the amino acid sequences for diphtheria toxin fragments A and B (Met -Thr387)-His. followed by the

sequences for IL-2 (Alai-Thriss). The fusion protein has a molecular mass of 58.000 Da. We can think of this large salem as a molecule of diphtheria toxin in which the rcceptIlt-binding domain ha.s been replaced by IL-2 sequences. ihereb> changing its binding specificity. Cells that express the high.alTinity IL-2 receptor bind the protein tightly. The IL-2 component is used as a director to bring the

species in contact with tumor cells. The diphtheria snun inhibits cellular protein synthesis and the cells die. Malignant cells in certain leukemias and lymphonnas. includ-

ing cutaneous T-cell lymphoma. express the high-affinity Il.-2 receptor on their cell surfaces. It is these cells that tknilcukun diftitox targets.

Denileukiun diftitox is indicated for the treatment olpersisteni or recurrent cutaneotus T-cell lymphoma whose malig1:1111 cells express the CD25 component of the IL-? receptor.

Denileukin dittitox is supplied as a frozen solution in

183

thrombocylopenia. Efficacy has been demonstrated in persons who have experienced severe thrombocytopenia following a previous chemotherapy cycle. Oprelvekin causes many adverse reactions. Among these are edema. neutropenic fever, headache, nausea and/or vomiting. dyspnea. and tachycardia. Patients must be monitored closely.

Oprelvekin is supplied as a lyophilized powder for reconstitution. Excipicnts include glycine and phosphate buffer components. The powder has a shelf life of 24 months. It should be stored at 2 to 8°C. If it is frozen, thaw it before reconstitution.

Tumor Necrosis Factor (Recombinant).t33l35 The TNFs (Etanercept. Enhrel) are members of a family of cytokines that are produced pritnarily in the innate immune system by activated mononuclear phagocytes. Along with ILl. TNF is typically the first cytokine to be produced upon infection, and its reactions can be both positive and negative. On the one hand. TNF can cause cytotoxicity and inflammation, and on the other hand, it serves as a signal to the adaptive immune response. The TNFs are all endogenous pyro-

gens. and they cause chills, fever. and flu-like symptoms. There are two forms of TNF: TNF-a (eachectin) and TNF/3 (Iymphotoxin). Both bind to the same receptor and cause similar effects. Etanercept is a dimeric fusion protein consisting of the extracellular ligand-hinding portion of the human 75-kDa

(p75) TNF receptor (TNFR) linked to the Fe portion of human isotype IgGi. The Fe component of etanercept contains the domain, the CH3 domain, and the hinge region,

water for injection. It should be stored at — 10°C or colder. his suggested that the vials be thawed in a refrigerator at 2 ii for less than 24 hours or at room temperature for

hut not the Cl-I1 domaiti of IgG1. These regions are responsible for the biological effects of irnrnunoglohulins. Etanereept

a 2 hours. Prepared solutions should be used within 6 hours. The drug is administered by IV infusion from a hag

peptide chain of 934 amino acids and has a molecular mass of approximately ISO kDa. It hinds specifically to TNF and blocks its interaction with cell surface TNFRs. Each etanercept molecule hinds specifically to two TNF molecules in the

I

ii

a syringe pump.

Oprelvekin. Netusega. is recombinant human Il_-Il that is expressed in a tecaitihinunt strain of E. cob as a thiorcdoxin and/or rhiLOprelvekin

fusion protein. The fusion protein is cleaved and purilied 1 obtain the rhIL- II protein. The protein ix 177 amino acids in length and has a mass olapproximately 19.0(X) Da. Oprel-

differs front the natural I 78-amino acid IL-Il by lacking an N-terminal proline. This alteration has not resulted iii differences itt bioactivity either in vitro or in vivu. IL.l lisa thromhopoietic growth factor. It directly stimulates the proliferation of hetiiatopoietic stem cells as well as nicgakaryocyte progenitor cells. This process induces mcgasarsuicyte maturation and increased production of platelets. Die primary hettuatopoictic activity of oprelvekin is stimulation of megaknryocytopoiesis and thrombopoiesis. Primary

and mature osteoclasts express mRNAs for both

IL-Il and its receptor. IL-Il K alpha. Hence, both honeiomiing attd houue-resorhing cells are possible targets for ILOprelvekin is

indicated for the prevention of severe It reduces the need for platelet transfu-

unyclosuppressive chemotherapy itt patients with i'iiiiiiwetuid malignancies who are at high risk for severe

is produced in recombinant CHO cultures. It consists of a

synovial fluid of rheumatoid arthritis patients. It is equally efficacious at blocking TNF-a and TNF-f3. The drug is indicated for reducing signs and symptoms and inhibiting the progression of structural damage in patients with moderately

to severely active rheumatoid arthritis. Etanercept is also indicated for reducing signs and symptoms of moderately to severely active polyarticular-course juvenile rheumatoid arthritis in patients 4 years of age and older who have had an inadequate response to one or more disease-modifying antirheumatic drugs (DMARDS. Etanercept is also indicated for reducing signs and symptoms of active arthritis in patients with psorlatic arthritis.

ENZYMES

Blood-Clotting Factors The blood clotting system of the human body is typically in it carefully balanced homeostatic state. If damage occurs to a blood vessel wall, a clot will foms to wall off the damage SO that the process of regeneration can begin. Normally this process is highly localized to the damaged region. so that

184

IViLson

and Gi.vtvldx Te.vthook of Organic Medicinal and Phar,naet'uiieal chemistry

the hemostatic response does not cause thrombi to migrate to distant sites or persist longer than it is needed. Lysis of blood clots occurs through the conversion of pla.sminogen to plasmin. which causes librinolysis. converting insoluble fibrin to soluble fibrinopeptides. The plasminogen—plasmin conversion is catalyzed by several blood and tissue activators. among them urokinase. kallikrein. plasminogen activators, and some undefined inhibitors. More specifically, the conversion of plasminogen to plasniin is catalyzed by two extremely specific serine proteases: a urokinase plasmino-

gen activator (uPA) and a tissue plasminogcn activator (tPA). This section focuses on tPA. Human IPA is a serine proeasc that is synthesized in the vascular endothelial cells, It is a single-chain peplide composed of 527 amino acids and has a molecular ma.ss of approximately 64,000 Da. About 7% of the mass of the molecule consists of carbohydrate. The molecule contains 35 Cys residues. These are fully paired, giving the tPA molecule 17 disulfide bonds. There arc four N-linked glycosylation sites recognized by consensus sequences Asn-X-Ser/Thr at residues 117. 184. 218. and 448. It is suspected that

bears

an 0-fucose residue. There are two forms of tPA that differ

by the presence or absence of a carbohydrate group at Asp184. Type I tPA is glycosylated at Asn117. and while type II cPA lacks a glycosyl group at Asn215 is typically unsubstituted in both forms. Asn11-, contains a high-munnose oligosacchande. while Asn substituents 184 and 448 are complex carbohydrate substituted. Dur-

ing the process of fibrinolysis the single-chain protein is cleaved between and lIe2Th by plasmin to yield 2chain tPA. Two-chain cPA consists of a heavy chain (the A

chain, derived from the N terminus) and a light chain (B chain), linked by a single disulfide bond between and Cys395. The A chain bean. some unique structural features: the finger region (residues 6 to 36). the growth factor region (approximate residues 44 to 80). and two kringle domains. These domains are disultide-closed loops, mostly sheet in structure. The finger and kringle 2 arc responsible for tPA binding to librin and for the activation of plasminogen. The

function of kringlc I is not known. The B chain contains the serine protease domain that contains the His-Asp-Scr unit that cleaves plasminogen.

Tissue Plasminogen Activator, Recomblnant.13& 137 tPA (recombinant). alteplusc (Activase). is identical with endogenous tPA. rtPA lacks a glycosyl residue at At

one time. rIPA was produced in two-chain form in CHO cultures. Now, large-scale cultures of recombinant human melanoma cells in fermenters are used to produce a product that is about 80% single-chain rIPA. Alteplase is used to improve ventricular function following an acute myocardial infarction, including reducing the incidence of congestive heart failure and decreasing mortality. The drug is also used to treat acute ischemic stroke after computed tomography (CT) or other diagnostic imaging has ruled out intracranial hemorrhage. rtPA is also used in cases of acute pulmonary thromboembolism and is being investigated for unstable angina pectoris. Alteplase is supplied ax powder for injection, and in recon-

stituted form (normal saline or 5% dextrose in water) is intended for IV infusion only. The solution expires in 8 hours at room temperature and must be prepared just before use.

Reteplase. Reteplase (Retavase) is a deletion mutant variant of tPA that is produced in recombinant E. coli. The deletions are in domains responsible for half-life. fibrin affinity. and thrombolytic potency. It consists of the kringle2 domain and protease domain of cPA but lacks the kringle. I domain and the growth factor domain. It is considered a third-generation thrombolytic agent and has a mechanism of action similar to that of alteplase. Reteplase acts directly by catalyzing the cleavage of plasminogen and initiating thrombolysis. It has high thrombolytic potency. A comparison of alicplasc and reteplase is given in Table 6-9.

Tenecteplase.13' Tenecteplase is a iPA produced by recombinant CHO cells. The molecule is a 527-amino acid glycoprotein developed by introducing the following modifications to the eDNA construct: Thr,05 to Asp. to Gin, both within the kringle-l domain, and a tetraulanine substitution at amino acids 296 to 299 in the protease do.

main. The drug is a sterile. lyophilized powder recommended for single intravenous bolus administration after re-

constitution with sterile water. Tenecteplase should he administered immediately after reconstitution.

Factor Antihemophilic factor VIII (recomhi• nant). Recombinate. Kogenate. Biociate. Helixate. is plasma protein that functions in the normal blood-clotting a

cascade by increasing the V,rn. ftr the activation of clotting factor X by factor IXa in the presence of calcium ions and negatively charged phospholipids. Factor VIII is used in the treatment of hemophilia A. Hemophilia A is a congenital disorder characterized by bleeding. The introduction of factor VIII as a drug has improved the quality of life and the life expectancy of individuals with this disorder. Unfonunately. it ha.s been necessary to rely on an unsure soulce (human plasma) for the factor. Exposure of patients to alaantigens and viruses has been a concern. Factor VIII derived from a recombinant source will potentially eliminate man) of these problems and provide an essentially unlimited supply of the drug. Factor VIII is biosynthesized as a single-chain polypeptide of 2.332 amino acids. The protein is very heavily glycosylated. Shortly after biosynthesis. peptide cleavage occurs and plasma factor VIII circulates as an 80-kDa light dian associated with a series of heavy chains of approximate)> 210 kDa in a metal ion-stabilized complex. Factor VIII pos sesses 25 potential N-linked glycosylation sites and 22 residues. The 2l0-kDa heavy chain is further cleaved b> proteases to yield a series of proteins of molecular mass

TABLE 6—9 ComparIson of the Pharmacokinetic Parameters of Alteplase and Reteplase Phamiacokinetic Parameter Effccllvc

(minutes)

Alteplase 5

Reteplas. Is—Is

Volume of distribution (L)

8.!

5

Pb.sma clearance (mI/mitt)

360—620

250-450

Chapter 6 u ISw:e(!,,ioIogv and Drug Discovery $8 kl)a. The 90- to 188-kDa protein molecules form a reid ion-stahili,.ed complex with the light chain. Recombinant factor VIII is produced in two recombinant in hatch culture of transfccted CHO cells or in coniIwous culture of baby hamster kidney (BHK) cells. There ac four types of recombinant factor VIII available. All four ire pnduced by inserting a cDNA construct encoding the curse peptide sequence into the CHO cell or BHK cell line. c

The Cl-to cell product contains a Galaf l—.3lGal unit. cshcre.is the BilK enzyme does not. Recombinant factor VIII is pohdicperse. containing multiple peptide homologues inchiding an 80-kDa protein and various modifications of an

90-kDa subunit protein. The product contains no blood pmducts and is free of microbes and pyrogens. Recirnihinant factor VIII is indicated for the treatment of classical hemophilia (hemophilia A) and for the prevention Ireatnient of hemorrhagic episodes and perioperative management of patients with hemophilia A. The drug is also indicated for the treatment of hemophilia A in persons who psse.ss inhibitors to factor VIII. Recombinant factor VIII is supplied in sterile, single-dose slaTs. Thu product iii stabilized with human albumin and The product must be stored at 2 to 8°C. without lfceoulg. In some instances the powder may be stored at irwin lelllperature for up to 3 months without loss of biologicii activity. Shaking of the reconstituted product should be isoslud because of the presence of the albumin. The drug he administered by intravenous bolu.s or drip infusion within 3 hours of reconstitution.

Since trace amounts of mouse or hamster protein may with recombinant factor VIII, one should he cauloSs when administering the drug to individuals with known hypersensitivity to plasma-derived antihemophilic factor or with hypersensitivity to biological preparations with trace mourns of uitouse or hamster proteins.

When a percon is deficient in clotting factor IX (Christmas factor), he—

iruphilia B re.sults. Hemophilia B affects primarily males

185

Drotreco gin Alfa.'4'

About 750,000 people are diagnosed with sepsis in the United States each year. and of these, an estimated 30% will die from it. despite treatment with intravenous antibiotics and supportive care. Patients with severe sepsis often experience failures of various systems in the body. including the circulatory system, the kidneys, and clotting. Drotrecogin alfa (activated), rotrecogin alfa (activated) (Xigris). is a recombinant form of human activated protein C. Activated protein C exerts an antithrombotic effect by inhibiting factors Vu and VIlla. In vitro data indicate that activated protein C has indirect profibrinolytic activity through its ability to inhibit plasminogen activator

inhibitor-I (PAl-I) and to limit generation of activated thrombin-activutable tibrinolysis inhibitor. Additionally, in vitro data indicate that activated protein C may exert an anti-inflammatory effect by inhibiting TNF production by unonocytes, by blocking leukocyte adhesion to selectins, and

by limiting the thrombin-induced inflammatory responses within the microvascular epithelium. Vials of drotrecogin alfa should be stored at 2 to 8°C without freezing. The reconstituted solution is stable for 14 hours at 25°C.

Anticoagulant Lepirudin.

Leeches (Hirudo medicinails) have been used medicinally for centuries to treat injuries in which blood engorges the tissues. The logic behind this is solid: leeches produce an agent known as hirudin that is a potent. specific thrombin inhibitor. Leeches have been used to prevent thrombosis in the microvasculature of reattached digits. Lepirudin (Refludan) is a rDNA-dcrived protein produced in yeast. It has a molecular mass of approximately 7,000 Da. Lepirudin differs from the natural polypeptide. in that it has an N-terminal leucine instead of isoleucine and is missing a sulfate function at

Otber Eniymes

irid accounts for about 15% of all cases of hemophilia. Treat-

Recombinant Human Deoxyribonuciease I

neni iuusolves replacement of factor IX so that the blood will clot. Recombinant coagulation factor IX (BeneFix) is a highly purified protein produced in recombinant CHO cells. free of blood products. The product is a glycoprotein of nalecutar mass approximately 55.000 Da. It consists of 415 inrtno acids in a single chain. The primaty amino acid wequenccofBeneFix is identical with the Ala1.,5 allelic form of plasria-iierived factor IX. and it has structural and functional characucristies similar to those of the endogenous protein. The recombinant protein is purified by chromatography. folowed by membrane filtration. SDS-polyacrylamide gel ckcrnuphoresis shows that the product exists primarily as a

DNAse is a human endonuclease, normally present in saliva, urine, pancreatic secretions, and blood. The enzyme catalyzes the hydrolysis of cxtracellular DNA into oligonucleo-

sngte component.

Clotting factor IX. recombinant, is indicated for the conmci arid prevention of hemorrhagic episodes in persons with hemophilia B (Christmas' disease), including the control and presention of bleeding in surgical procedures.

tides. Aerosolized recombinant human DNAse (rhDNAse). dornase alfa, Pulmozyme, has been formulated into an inhalation agent for the treatment of pulmonary disease in patients with cystic fibrosis (CF). Among the clinical manifestations of CF are obstruction of the airways by viscous, dehydrated mucus. Pulmonary function is diminished, and microbes can become entrapped in the viscid matrix. A cycle of pulmonary obstruction and infection leads to progressive lung destruction and eventual death before the age of 30 most CF patients. The immune system responds by sending in neutrophils, and these accumulate and eventually degenerate, releasing large amounts of DNA. The high levels of extracellular DNA released and the mucous glycoproteins are responsible for the degenerat-

BeneFix is supplied as a sterile lyophilized powder. It

ing lung function. The DNA-rich secretions also bind to

should be stored at 2 to 8°C. The product will tolerate storage

aminoglycoside antibiotics typically used to treat the infections. In vitro studies showed that the viscosity of the secretions could be reduced by application of DNAse I. Before DNAse was purified and sequenced from human

at

temperature not above 25°C for 6 months The drug unstable following reconstitution and must be used

wIthin 3 hours.

186

Wi/con

and Gi.ccohi '.c

of ()r,c,'anie Medic'i,ial and Pharmaceutha! ChernLs,rv

sources, a partial DNA sequence from bovine t)NAse (263 amino acids) was used to create a library that could he used to screen a human pancreatic DNA library. This facilitatcd the development of the human recombinant protein. The endogenous human and recombinant protein sequences are identical. Recombinant human deoxyrihonuclease I irhDNAse) was cloned, sequenced. and expressed to examine the potential

given here. Vaccine production is a natural application of rDNA technology, aimed at achieving highly pure and efficacious products. Currently, there are four rDNA vaccines approved for human use. A number of others are in clinical trials for some rather exotic uses. It would appear that biotechnological approaches to vaccines will bring about some very useful drugs.

of DNAse I as a drug for use in CF. It has been shown that cleavage of high-molecular-weight DNA into smaller

PRODUCTS

fragments by treatment with aerosolited rhDNAse improves the clearance of mucus from the lungs and reduces the exacerbations of respiratory symptoms requiring parenteral antibiotics.

rhDNAse lisa monomeric glycoprotcin consisting of 260 amino acids produced in CHO cell culture. The molecule possesses four Cys residues and two sites that probably con-

tain N-linked glycosides. The molecular mass of the molecule is about 29 kDa, DNAse I is an endonuclease that cleaves double-stranded DNA (and to sonic extent singlestranded DNA) into 5'-phosphate-terminated polynucleotides. Activity depends on the presence of calcium and magnesiuni ions. Pulmozyme is approved (icr use in the treatment of CF patients. in conjunction with standard therapies. to reduce the frequency of respiratory infections requiring parenteral antibiotics and to improve pulmonary function. The dose is delivered at a level of 2.5 mg daily with a nchuli,er. Pulmo,.yme is not a replacement for antibiotics. bronchodilators. and daily physical therapy. Type I Gaucher's disease is a hereditary condition occurring in about 1:40.0(X) individuals. It is characterized by a functional deficiency in enzycne activity and the resulting accumulation of lipid glucocerebroside in tissue macrophages. which become engorged and are termed Gaudier s (c/is. Gaucher's cells typically accumulate in the liver, spleen. and bone marrow and. occasionally, in lung. kidney. and intestine. Secondary hematological sequelae include severe anemia and throinbocytopenia in addition to characteristic progressive hepatosple-

cerezyme.

nomegaly. Skeletal complications are common and are frequently the most debilitating and disabling feature of Gaucher's disease. Possible skeletal complications are oxteonecrosis. osteopenia with secondary pathological fractures. remodeling failure. osteosclerosis. and hone crises. Cerezyme (Imiglucerase)'44 is a recombinant, macrophage-turgeted variant 01' human $-glucocerebrosidase. punfled from CHO cells. It catalyzes the hydrolysis of the glyco-

lipid glucocerebroside to glucose and ceramide follosving the normal degradation pathway for membrane lipids. Cerezyme is supplied as a lyophilized powder for reeotistitution. The powder should be stored at 2 to 8°C until used.

The reconstituted product for IV infusion is stable for 12 hours at room temperature.

VACCINES Vaccines and immunizing hiologicals are covered thoroiivhlv in Chaoter 7 of this text, so no lengthy discussion is

Recombivax and Engerix-B.'45

Recombivax and Engerix-B are interchangeable for immunization against hepatitis 13 virus (I-IBV. serum hepatitis). I3oth contain a 226amino acid polypeptide composing 22-nm-diameter particles that possess the anhigenic epitopes of the HBV surtlict coat (S) protein. The products from two manufacturers arc expressed from recombinant S. e'erevisiae. It is recommended that patients receive 3 doses, with the secotid dose I month after the first and the third dose 6 tiionths after the first. The route and site of injection are IM in deltoid muscle or. tar infants and young children, in the anterolateral thigh.

The vaccines achieve 94 to 98% immunogenicity amont adults 20 to 39 years of age I to 2 months alter the third dose. Adults over 40 years of age reach 89% immunogenic. ity. young children, and adolescents achieve 96 to 99r4 immunogenicity. The vaccine is supplied as a suspension adsorbed to alumi-

num hydroxide. The shelf life is 36 months. The vaccine should be stored at 2 to 8°C and should be discarded if Ira.'.en. Freezing destroys potency. l.yme disease is caused by the spirochete Liorrelia burgdo,frri. The microorganism is transmitted pci. niarily by ticks and is endemic in heavily wooded areas and forests. The disease produces arthritis-like symptoms. A cine against Lyine disease was created by developing a combinant E. that contains the gene for the bacterial outer surlicce protein. This protein (OspA) is a single peptide chain of 257 amino acids with covalently bound lipids at the N terminus. The vaccine is formulated as a suspetision with alutnintttn hydroxide as an adsorption adju. vant. In testing. subjects between IS and 70 years with 3 doses of LYMErix at 0, I. and 12 months demon.

strated a 78% decrease in the likelihood of infection. LYMEr1x has a shelf life of 24 months. It should he stored

at 2 to 8°C and must he discarded if frozen, If necessar), the vaccine can tolerate 4 days at room temperature. C'omvax. Comvax is a combination of llaeinophilm in fluenzae type b conjugate and hepatitis B (recombinant). Ii was recently approved by the Advisory Committee on fin munization Practices (ACIP). Each 0.5-mL dose containc 7.5 of H. inj1sa'nzae type h polyribosylnibitol (PRP). 125 of Nejsse'rja ineningitidis outer membrane protein complex (OMPC). and 5 of hepatitis B surface antigen (HhsAg) on an aluminum hydroxide adjuvant. 'fix Committee on Infectious Diseases, the American of Pediatrics, and the Advisory Academy of Family Phyci cians recommend that all infants receive the vaccine. doses should be administered at ages 2. 4. and 12 to months. The vaccine should not be administered to infants younger than 6 weeks because of potential suppression c

Chapter 6 • Biotechnology and !)nig Discoi'erv

TABLE 6-10 Vaccines Developad

Using Biotedinology Type

Vaccine

Use

Phase of Development

Vaccine

Breast. cotorectal. lung cuncers: nielanoma; saucoma

II

Vuccjnc

Metaslalic melanono

It

Vaccine

Multiple mycloma

It

Ibsirna-densed diotvpie Ag vaccine

Vaccine

Multiple niyelisma

'tsLssn: rudinuma lherncciric,

Therapeutic vaccine

Stage 4 malignant melanoma

U \t1F- 2 I 7))-. 7))

nid.ssoma sgci.-inc

II 5)11

187

I

lit

vaccine

therapeutic vuceinc

NHl-o)24

vaccine F vaccine

ii

Hepatitis

prophylanii.

Li

Vaccine

Group A streptococci, including nccrotiting Iasciitiv, strep tiiroai. and rheumatic icvcr

it

Vacdnes In Development Qnilc a number of biotechnology-generated vaccines arc in dcclllpnicnt (Table 6-10). Some of them are in the category

These vaccines are designed to

hind to cellular receptor. endogenous molecules, and so on. pnslucing specific pharmacological effects. For example, if has a particular receptor that binds a ligand to activate ihe cell. binding an antibody raised by a specific vaccine to receptor will prevent activation. If a tumor has a requirerent for such a receptor—ligand binding. using a vaccine to delelop antibody to the receptor or the ligand should prevent 'r slow cellular proliferation.

PREPARATION OF ANT(BODIES147 149

Ilybridoma (Monodonal Antibody [Mab]) TechnIques

a humor-ji immune response. H-lymphocyte-derived cells produce antibodies with variations in chemical

Iructure. Biologically, these variations extend the utility of the secreted antibody. These variations are caused by affinity maturation, the tendency for the affinity of antibody for anti-

ecu to increase with each challenge, and mutation at the lithe of somatic recombination. These phenomena produce jniilwdies with slightly different speciticitics. Because the clones of antibody-producing cells provide more than one lnjcturjl type of antibody, they arc called polyclonal antslvdirn. Another type of antibody consists of highly homogeUcI)Us populations of hybrid proteins produced by one clone f specially prepared B lymphocytes. These antibodies, lack-

op structural variations. arc highly "focused" on their anticcthic counterparts' determinants or epitopes. and arc called 71,hhsii/)hhhul.

inkctii,n

ill

Recnntbinaiil subunit vaccine

months.

In

Gnstrocsaphageai rellun disease

Cellular vaccine

immune response to PRP-OMPC with subsequent doses ('tsmvax TM. The series should be completed by I 2 to

therapeutic vaccines

ii

I diabetes

Vaccine

Ca.'nn therapeutic vaccinc

A problem with creating MAbs is that one cannot simply prepare an antibody-producing H lymphocyte and propagate it. Such cells live only brietly in the laboratory environment. Instead, antibody-producing cells are fused with an immortal

(tumor) cell line to create hvbriduinas—long-lived. antibody-secreting cells. The trick is to select the monoclonal cells that produce the desired antibody. The hybridoma technique ha,s opened the door to new therapeutic antibodies. imaging agents, radiological diagnostic test kits, targeted radionuclide delivery agents, and home test kits.

In the hybridoma method (Fig. 6-14). a mouse or other small animal is sensitiied with an antigen. When a high enough titer of antibody against the selected antigen has been attained, the animal is sacrificed and its spleen cells are collected. The spleen cells contain a large number of B lymphocytes. and it is certain that some will he able to produce antigen-specific antibodies. Because the spleen cells are normal B lymphocytes, they have a very short lifetime in cell cultures. Therefore, a method must be used to extend their lifetime. To produce MAbs, B cells are fused with immortal myeloma cells in the presence of lusogens such as polyethylene glycol. This procedure produces genetically hall-normal and

half-myeloma cells. Since the niyelonta cells arc immortal. the longevity problem is solved. The selcction process depend.s on two different myeloma cell lines: one lacking the enzyme hypoxanthine-guanine phosphoribosyl transferase (HGPRT). a key enzyme in the nucleotide salvage pathways. and the other lacking the Th gene, a key gene in the pyrimidine biosynthetic pathways. The spleen H cells arc HGPRT

and Tk (+1, while the myeloma cells are HGPRT and Tk (—). This mycloma cell line cannot survive in a medium containing aminopterin, a thymidylate synthetasc inhibitor. because it cannot synthesice pyrimidines. The HGPRT (—) cell line cannot use the purine salvage pathways to make

nucleotides. lotting it to use thyinidylale synthetuse. With thymidylate synthetase inhibited, the cell dies. After fusion. cells arc maintained on a medium containing hypoxunthine. aminopterin. and Ihymidine (HAT). Only cells that are "cor-

188

Wilson and Gisvoids Textbook of Organic Medicinal and Pharmaceutical Chemistry

Ag sensitization of mouse

•O

2. Isolate mouse spleen cells

+

(I) I

• 0

4.Cellfuston

t:•

I

I

I

I

t:•

5, Hybridoma selection In

HAT medium

I

I

I

I

000000000000 ooooooo•oooo oooo•ooooooo 000000000000 oooooo•ooooo I

00000000

3. HPRT (—)

myeloma cells

6. Ab screenIng

00

OOS0000 96S 00

( 7. Selection of Ab(+) clones 8. Prollleratlon

+ 10. Monoclonal Abs from ascites

9. Monoclonal Abs (mm cell culture medium

Purification

Punficabon

FIgure 6—14 u General method for preparation of monodonal antibodnr, using hybridomas and HAT medium antibody; Ag. antigen.

rectly" fused between one spleen cell (HGPRT +]) and

(known as HAMA) ha.s tended to limit the use olmonoclora!

one myeloma cell (immortal). i.e.. a hybridoma. can survive

in human therapy. In developing a method for making MAbs useful in Is mans, it is necessary to remove the mouse characteristics from the MAb. The antigen-recognition is gion (Fab) of the MAb must retain its ability to bind to antigen. however, If this feature is altered, the antibody nil likely be useless. Within the light and heavy chains of b Fab portions of antibody molecules arc regions that called complementarity'de:ermining regions or CDRs.

in HAT medium. Fused myeloma cells (myeloma—rnyeloma) lack the correct genes and cannot survive. Fused spleen cells (spleen—spleen) cannot grow in culture. Thus, only the fused hybridomu (myeloma—spleen) survives. Hypoxanthine and thymidine furnish precursors for the growth suppresses eelts that of HG?RT (+ 1 ceVts. failed to fuse. Hybridomas can be isolated in a 96-well plate and transferred into larger cultures for proliferation, The cul-

ture medium will eventually contain a high concentration of MAb against the original antigen. This antibody can be purified to homogeneity. Monoclonal antibodies, being proteins, tend to be highly

chain possesses three of the.se. One of the CDRs. CDR3.

immunogenic in humans. This is especially true of the MAbs produced in mouse culture. Humans begin to develop antibodies to mouse MAbs after a single dose. This is natural. The human host is mounting an antibody response to a for-

trated there. These must be intact for specific antigcn-ans body binding. Immune responses against murine MAb r:

eign antigen. The human antimouse antibody response

located at the juncture of the variable and common domais

CDR3 is also referred to as the hypervariable region most of the variability of the antibody molecule is

directed against not only the variable regions, but constant regions. Hence, to decrease the immunogenicil) an MAb one must create antibodies that have been

Chapter 6 U Biau'chuo!ugv and Drug

ized." In MAI production. usually the

and V1 domains of a human antibody are replaced by the corresponding reglans from the mouse antibody, leaving the specificity intact. hut using human constant regions that should not be immunogenic. Antibodies like these are called numeric, and they ate less immunogenic and have a longer half-life in human patients. Examples of chimeric MAbs are abciximub. rituximab. iniliximab. and basiliximab. Methods are available for the development of MAbs with 95 to 100% human sequence. By using transgenic mice, all of the essential human antibody genes can he expressed.

Monodonal AnUbody Drugs Rituximab.'50' 151

Rituximab (Rituxan. Chimeric) is an MAb directed against the CD2O antigen expressed on the of normal and malignant B lymphocytes. The MAb k produced in mammalian (CHO) suspension culture and is achimeric (nwrine/human) MAb of the lgG1 type. The protein is composed of murine light and heavy chain variable regions and human constant regions. Rituximab is indicated fur the treatment of patients with relapsed or refractory. low-

grade or follicular. CD2O( +) B cell non-Hodgkin's lymphoma. Rituximab binds specifically to antigen CD2O human B-lymphocyte-restricted differentiation antigen, a hydrophobic transnrembrane protein expressed on pre- and mature-B lymphocytes). CD2O is a protein of 35 to 37 kDa. and it may play a role in B cell activation and regulation and may be a calcium ion channel. The antigen is also cxpressed on more than 90% of non-Hodgkin's lymphoma B cells hut is not found on hematopoietic stem cells. pro-B or other normal tissues. CD2O cells, normal plasma regulates the early steps in the activation process for cellcycle initiation and differentiation. Gemtuzumab

153

Gennuzunsab

fanricin (Mylotarg. fusion molecule) is an MAb derived from the CD33 antigen, a sialic acid-dependent adhesion protein expressed on the surface of leukemia blasts and im-

mature normal cells of myelomonocytic origin but not on

189

rivativc is released inside the lysosomes of the myeloid cells.

The released calicheamicin derivative binds to the minor groove of DNA and causes double-strand breaks and cell death. 155 Alemtuzuniah (Cumpalh) is humanized MAb (Campath- I H) that is directed against the 21-

to 28-kDa cell surface glycoprotein CD52. CDS2 is expressed (In the surface of normal and malignant B and T lymphocytes. NK cells. naonocytes. mztcrophages. and nissties of the male reproductive system. The Canipath- I H antibody is an lgG1 K form with humanized variable and constant regions and CDRs from a rat MAb. Campath-IG.

Alemtuzumah is indicated for the treatment of B-cell chronic lymphocytic leukemia in patients who have been treated with alkylating agents and who have failed on this therapy. Alemnuzumab binds to CD52. a nonmodulating antigen that is present on the surface of essentially all B and

T lymphocytes: most monocytes. niacrophages. and NK cells: and a suhpopulation of granulocytes. The proposed mechanism of action is antibody-dependent lysis of leukemic cells following cell surface binding. Ralixiniab (Simulect. Chimeric) is an MAb produced by a mouse monoclonal cell line that has been engineered to produce the busiliximah lgG1 antibody glycoprotein. The product is chimeric (murine/human). Basiliximah is indicated for prophylaxis of acute organ rejection in patients receiving renal transplantation when used as part of a regimen of immunosuppressants and corticosteroids. Basiliximab is also indicated in pediatric renal transplantation. Basiliximab specifically hinds to the lL-2 receptor achain (the CD2S antigen, part of the three-component IL-2 receptor site). These sites arc expressed on the surfaces of activated T lymphocytes. Once hound it blocks the lL-2a recep-

tor with extremely high affinity. This specific. high-affinity binding to IL-2a competitively inhibits lL-2-mcdiatcd activation of lymphocytes, a critical event in the cellular immune response in allogralt rejection.

satins! hematopoietic stem cells. CD33 binds sialic acid and

to regulate signaling in myeloid cells. The antibody sreconrhinant. humanized lgG3 K. linked with the cytotoxic

anutumor antibiotic ozogamicin ((mm the calicheamicin family). More than 98.3% of the amino acids of genituzumab are of human origin. The constant region of the MAb conrains human sequences. while the CDRs derive from a mutine antibody that binds CD33. The antibody is linked to Nrcelvl-y-calicheamicin via a bifunctional linker. Cemtuzumah ozogamicin is indicated for the treatment of patients with CD33-lxssitive acute myeloid leukemia in first elapse utliong adults 60 years of age or older who are not considered candidates for cytotoxic chemotherapy. Gemtuzuinah ozogamicin binds to the CD33 antigen cxby hcmatopoietic cells. This antigen is expressed on he surface of leukemic blasts in more than 80% of patients

Daclizumab.159' 160

Molecularly. daclizumab (Zetapax. Chimeric) is an imniunoglobulin G (lgG1) MAb that binds specifically to the a subunit of the lL-2 receptor (the complete. high-affinity activated IL-2 receptor consists of interacting a. and y subunits). IL-2 receptors are expressed on the surfaces of activated lymphocytes, where they

mediate lymphocyte clonal expansion and differentiation. Daclizumab is a chinieric proteiti (90% human and 10% mouse) IgGu. The MAb targets only recently activated T cells that have interacted with antigen and have developed from their naïve lirm into their activated form. It is at this time that the lL-2 receptors are expressed. The human amino acid sequences of daclizumab derive from constant domains

of human lgG. and the variable domains are derived from the fused Eu myelorna antibody. The murine sequences de-

rise from CDRs of a mouse anti-IL2a antibody. The indications for dacli,uniah are prophylaxis of acute

sith acute myeloid leukemia. CD33 is also expressed on nunnaf and Icukemic mycloid colony-forming cells. includng kukemic clonogenic precursors, hut it is not expressed

organ rejection in patients receiving renal transplants, as part

srplunpotetn heniatopoietic stem cells or nonhematopoietic Binding of the ant i-CD33 antibody results in a complex hat inlernali,.ed. On internalization the calicheanuicin de-

of an immunosuppressant regimen including cyclosporine and corticosteroids. The mechanism of action is the same as that of basiliximab.

190

Wi/so,, wul Gis,y,hPs Tt's,hook of Organic Medicinal and PF,ar,nace,uical ('lu'niisfn'

Muromonah-CD3 (murine. Orthoclone-OKT3) is an unmodified mouse immunoglobulin. an monoclonal. It hinds a glycoprotein on the surface of mature I lymphocytes. Mature T cells have. as pan of the signal transduction machinery of the T-cell receptor complex. a set of three glycoproteins that arc collectively called CD3. Together with the protein zeta, the CD3 molecules become phosphorylaled when the 1-cell receptor is bound to a peptide fragment and the major histocompatibility complex. The phosphorylated CD3 and zeta molecules transmit information into the cell, ultimately producing transcription factors that enter the nucleus and direct the T-cell activ-

ity. By binding to CD3. niuron,onah-CD3 prevents signal transduction into T cells. Muromonah-CD3 blocks the function of T cells that are involved in acute renal rejection. Hence. it is indicated for the treatment of acute allograft rejection in heart and liver transplant recipients resistant to standard steroid therapies.

Abciximab.'"' 165 Abciximab (ReoPro, chimeric) is an MAb engineered from the glycoprotcin lib/Illa receptor of human platelets. The preparation is fragmented, containing

only the Fab portion of the antibody molecule. This MAb is a chimeric human—mouse immunoglohulin. The Fob fragments may contain mouse variable heavy- and light-chain regions and httman constant heavy- and light-chain regions.

Abciximub is indicated as an adjunct to percutaneous transluminal coronary angioplasty or athcrectomy for the prevention of acute cardiac ischcmic complications in patients at high risk far abrupt closure of a treated coronary vessel. Abciximah appears to decrease the incidence of myo-

cordial infarction.

Abciximah hinds to the intact GPllb/GPIIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet-specific receptors involved in aggregation. The antibody prevents platelet aggregation by preventing the binding of fibrinogen. the von Willebrand factor. and other adhesion molecules on activated platelets. The inhibition of binding to the surface receptors may be due to steric hindrance or conlormauonal effects preventing large molecules from approaching the receptor. Trastuzumab.'66' 767

Trastuzumab (Herceptin. human-

ized) is an MAb engineered from the hutnan epidermal growth factor receptor type 2 (HER2) protein. This MAb is a human —niurine immunoglobulin. II contains human structural domains (framework) and the CDR of a murine antiis the body (4D5) that hinds specifically to HER2. lgG, type structure, and the antibody is monoclonal. The protein inhibits the proliferation of human tumor cells that overexpress HER2. Trastuzumab is indicated for use as a single agent far the

treatment of patients with metastatic breast cancer whose tumors overexpress the HER2 protein and who have not received chemotherapy for their metastatic disease. The HER2 proto-oncogene encodes a transmembranc receptor protein of 185 kDa that is structurally related to the epidermal growth factor receptor HER2. Overexpression of this protein is observed in 25 to of primary breast cancers. Trastuzumab binds with high affinity to the extracellular domain of HER2. It inhibits the proliferation of human

tumor cells that overexpress HER2. Trastuzumab also mediates the process of antibody-mediated cellular cytotoxicity (A DCC). This process, leading to cell death, is preferentially exerted on HER2-overexpressing cancer cells over those that do not overexpress I-IER2. 169 The MAb infliximab (Remicade. chimend is produced from cells that have been sensitized with human TNF-a. The MAb is a chimeric human—mouse immunoglobulin. The constant regions are of human peptide sequence and the variable regions are murine. The MAb is

of type lgG, K. lafliximab is indicated for the treatment of moderately to severely active Crohn's disease to decrease signs and symptoms in patients who had an inadequate response to conven-

tional treatments. Inflixiniab binds specifically to TNFa. It neutralizes the biological activity of TNFa by binding with high affinity to soluble and Lransmemhrane forms 01' the TNF. Infliximab destroys TNFa-producing cells. An additional mechanism by which inflixim-ab could work is as follows: by inhibiting TNFa. pathways leading to IL-I and IL-6 are inhibited. These interleukins are inflammatory cytokines. Inhibiting their production blocks some of the inflammation common to Crohn's disease.

Monoclonal Antibody Radlonuclide Test

Kib

Arcitumomab."°

Arcitumotnab (CEA-Scan) is a marine monoclonal Fab' fragtnent of IMMU-4, an MAb generated in murine ascites fluid. Both IMMU-4 and arcitumnomal, react with careinocmbryonic antigen (CEA). a tumor-Mood-

ated antigen whose expression is increased in a variety of carcinomas, especially those of the GI tract. The preparation is a protein, tnurinc Ig Fob fragment from lgG,. for chemical

labeling with Tc-99m. Arcitumomabfl'c-99m is for use with standard diagnostic evaluations for detecting the presence, location, and extent of recurrent or metastatic colorectal carcinoma involving the liver, extrahepatic abdomen, and pelvts. with a histologically confirmed diagnosis. IMMU-4 (and the Fab' fragments of

arcitumomah) bind to carcinoembryonic antigen (CEA). whose expression is increased in carcinoma, Arcitumomabl Tc-99m is injected, and the radionuclide scan is read 2 toS hours later.

Nofetumomab Merpentan.'7'

Nofetumomab mc,pentan (Verluma Kit) is the Fob fragment derived t'rom the

murinc MAb NR-LU-lO. The product is a protein. tnonoclonal that has been fragmented from NR-LU-I0. Nofetumomab possesses only the Fab portion. NR-LU- It) aM nofetumomab are directed against a 40-kDa protein antigen that is expressed in a variety of cancers and some normal tissues.

Nofetumomab is indicated for the detection and cvalm• tion of extensive-stage disease in patients with biopsy-con firmed, previously untreated small cell lung cancer by scan. CT scan (head, chest, abdomen) or chest x-ray. Nofetuntomab merpentan possesses a linker and a chelator that binds the technetium to the peptide. This is a phenthioac ligand. 2.3.5.6-teu-afluorophenyl-4.5-bis-S-I I -ethoxycthyll-

thioacctoamidopentanoate. hence the name

tan.

Chapter 6 • fuiozeelinulogv and I)rn,ç' Di woven Pendetide.'72 Satumomab pendetide inurine) is a kit for In-Ill. Satumonnab is pre-

Satumomab

irom a marine antibody raised to a membranc-enriched euract of human breast carcinoma hepatic metastasis. It is and monoclonal. The MAb recoglgG, ni,cs tumor-associated glycoprotein (TAG) 72. a mucin-like with a mass greater than 100.00(1 Da. Satitmoniab is indicated as a diagnostic aid in detennining the extent and location of extrahepatic malignant disease in patients with known colorectal and ovarian cancer. This aeenl is used after standard diagnostic tests are completed and when additional information is needed. The cancer must lv recurrent or previously diagnosed by other methods. Satutnoma), localizes to TAG 72. The antibody is chemi-

modified so that it links to radioactive indium-Ill. ahich is mixed with the antibody just prior to injection.

191

MAb derived from an initial sensitization with CD2O antigen. expressed on the surface of normal and malignant B cells, The antibody is a murine IgG1 K subtype, directed against CD2O antigen. It is produced in a CHO cell line. Ibritumomab ii. indicated for use as a multistage regimen to treat patients with relapsed or refractory low-grade. Ibllicular. or transformed B-cell non-Hodgkin's lymphomu. including patients with rituximab-rel'ractory follicular non-Hodgkin's lymphoma. Ibritumomab tiuxetan binds specifically to CD2O antigen

(human B-lymphocyte-restricted differentiation antigen). CD2O is expressed on pre-B and mature-B lymphocytes and

on more than 90% of B-cell non-Hodgkin's lymphoma. When the CDR of ibritumomab tiutuxan binds to the CD2O antigen. apoptosis is initiated. The tiutuxan chelate binds

Imagine techniques will reveal the localization of the satu-

indium-Ill and yttrium-90 tightly. Beta emission induces cellular damage by forming free radicals in the target

iramab as "hot spots." To link the indium-Ill to the satuniomab protein, a linker-chelator is used. This is glycylI-(N*diethylenetriacnincpentaacetic acid)-lysine hy-

cells and neighboring cells. Tiutuxan is IN-12-bis(carboxy' meihyl)aminoj-3-(p-isothiocyanatophenyl)propyll-IN-12bis(earboxymethyl)aminoj2-(methyl)-ethyl glycine.

drochloride.

frndromab Pentetate.'73

lmciromab pentetate (mu-

nrc: Myoscint Kit for the preparation of indium-Ill imcironub pentelute) is a murine iinmunoglobulin fragment raised is the heavy chain of human myosin. The drug is a protein the clans. It is monoclonal, consisting of the Fabbinding fragmrnts only, and it is bound to the linker-chelator

diethyleneiriamine pentaacetic acid for labeling with indium-Ill. lmciromah binds to the heavy chain of human the intracellular protein found in cardiac and skcle41 muscle cells.

lmciromah pentetate is indicated for detecting the prcsence and location of myocardial injury in patients after a 'uspected myocardial infarction. In normal nsyocardium. intnacchular proteins such as myosin are isolated from the cxrasascular space by the cell membrane and are inaccessible oantib4xly binding. After myocyte injury the cell membrane oss integrity and becomes permeable to macromolecules.

In-Home Test Kits"6 There are a variety of MAh-bascd in-home test kits that are designed to detect pregnancy and ovulation. For example, a pregnancy test kit targets the antigen human chorionic gonadotropin and displays a certain sign if the test is positive.

The other type of test kit predicts ovulation by targeting luteinizing hormone in the urine. Just before ovulation. luteinizing hormone surges. The test kit is designed to detect based on and signal the time of ovulation. These test the complex techniques of MAbs. are designed to be as.sirnpIe and error-free as possible for patients.

GENOMICS a term that means "a study of genes and their functions." Currently. genolnics is probably the central Genornics177 is

'stick allows lmciroinab-ln- Ill to enter the cells. where it

driving force for new drug discovery and for novel treat-

hinds to intracellular myosin. The drug localizes in infarcted t;v,ucs, where radionuclide scanning can visualize it.

nnents for disease. Gene therapy is a concept that is often discussed. The human genome project. which was largely completed in the year 2000. provided over 4 billion base pairs of data that have been deposited in public databases. Sequencing the genome itself was an enormous task, but the correlation of genomic data with disease states, sites of microbial attachment, and drug receptor sites is still in its infancy. Once these problems are solved. genomic data will be used to diagnose and treat disease and to develop new drugs specifically for disease statc.s (and possibly specific for a patient). Studying the genetics of biochemical pathways will provide an entry into enzyme-based therapies. There will undoubtedly be a host of new targets for drug therapy. Because deciphering the inlonnation that the genomic sequence provides is a complex undertaking. these benefits are probably going to occur years in the future.

Pendetide.'74 Capromab (ProstaScint Kit ii the preparation of In-I II capromab pendetide. murine) an \IAb Iniurine lgG1 id that derives from an initial sensiCapromab

'i,ation with a glycoproicin expressed by prostate epithelium Inuwn as prostate .xurface inenibrane antigen (PSMA). The

recogniics PSMA specifically and thus is specific for adenocarcinomas, The drug is used in newly dinguiocd patients with proven prostate cancer who are at high rl.k pelvic lymph metastasis, PSMA has been found in Iluny primary and mciaistatic prostate cancer lesions. The

domain marker 7El l-CS.3 reacts with more kin 9V tif adenocarcinonnas evaluated.

To join the indium-Ill to the antibody, a linker-chelator 'aced. This moiety is glycyltyrosyl-(N-ethylenelriaminepeitaicelic acid)-lysine 1-ICI.

A Therapeutic Radlonudide Monodonal Ibritumomab (Zevalin kits to ln.l II Zevalin and Y-90 Zevalin, murine) is an

Ibjitumomab Tiuxetan.

Unraveling the Genomic Code t. Determine Structure-Function Relationships: Bloinfonnatics When considering the topic 01' hioinformatics. one must rec-

ognize that thin is a broad term covering many different

292

WiIcon

and Gisio!d.s 'texibook of Organie Medicinal and Pharniaceutica! clu'nsic:rv

plasma sulfadoxine concentration occurs in 2.5 to 6 hours, and the peak plasma pyrirnethantine concentration occurs in 1.5 to 8 hours. Resistance has developed, much of ii involving mutations in either or both of the genes coding dihydrotolate reductase and thymidylate synthase.

Atovaquone and Pro guanil HCI.

Atovaquone and proguanil HCI (Fig. 9-8) are administered in combination

(Malarone) in an atovaquone-to-proguanil HCI ratio of 2.5:1. measured in milligrams (not millimoles). Proguanil. developed in 1945. is an early example of a prodrug. It is metaboliLed to cycloguanil (Fig. 9-9). primarily by CYP

2C19. The polymorphic nature of this hepatic enzyme explains why certain suhpopulations do not respond to proguanil: they cannot convert proguanil to the active cycloguanil. The basis for this combination is two distinct and unrelated mechanisms of action against the parasite. Atovaquonc is a selective inhibitor of the PIas,nodiurn's mitochondrial electron transport system. and cycloguanil is a dihydrofolate reductase inhibitor. Atovaquone's chemistry is based on it

being a naphthoquinone that participates in duclion reactions as part of its quinone—hydroqttinon tern. It is patterned after coenzyme Q. found in

electron transport chains. The drug selectively inte with mitochondrial electron transport, particularly parasite's cytochrome he1 site. This deprives the needed ATP and could cause it to become anacnibic. tance to this drug comes from a mutation in the paia cylochrome. Cycloguanil (proguanil) interferes with deoxythymid synthesis by inhibiting dihydrofolate reductase (see F and the pyrimethamine discussion). Resistance to cycloguanil is attributed to amino acid changes drofolate reductase binding site. Its elimination hnlf.lrl to 72 hours> is much shorter than that of the other anna ial dihydrofolate reductase. pyrimethamine (mean din

tion half-life of Ill hours). The combinaticit is against both erythrocytic and exoerythrocytic Plussnsj

This drug combination is indicated for malaria chloroquine, halofantrine. mefloquine. and main site is the sporozoite stage (site liii Fig. 9.li.

H—N

H

/ H3C

Proguanlt (Chioroguanide)

H—N

\\/

'C —N/ / \

H

H

C—N "CH3

shifts

/

H

H

FIgure 9—9 • Conversion of proguanil to cydoguan Cydoguanlt (actIve metaboilte)

2C 19.

Chapter 6 • Biotechnology and Drug Discovery vanous points in the array are acquired in a computer for analysis. As an

example. we can consider two cells: cell type I. a healthy cell, and cell type 2, a diseased cell. Both cell types contain an identical set of four genes: A.B.C. and D. mRNA is isolated from each cell type and used to create fluorescenttagged cDNA. In this case, red and green are used. Labeled samples are mixed and incubated with a microarray that con-

tains the immobilized genes A, B, C, and D. The tagged molecules bind to the sites on the array corresponding to the genes being expressed in each cell. A robotic scanner, also a product of silicon chip technology, excites the fluorescent lahels. and images are stored in a computer. The computer can compute the red-to-green fluorescence ratio, subtract out background noise, and so on. The computer creates a table of the intensity of red to green fluorescence for every point in the matrix. Perhaps both cells express the same levels of gene A. cell I expresses more of gene B. cell 2 (the diseased cell) expresses more of gene C, and neither cell expresses gene D. This is a simplistic explanation; experiments have been reported in which as many as 30.000 spots have been placed in the microarray. DNA microarrays can detect changes in gene expression levels, expression patterns (e.g., the cell cycle). genomic gains and losses (e.g.. lost or broken parts of chromosomes

in cancer cells), and mutations in DNA (single nucleotide polymorphism ISNPsI). SNPs are also of interest because they may provide clues about how different people respond In a single drug in different ways.

word proteoine describes protein expressed by a geanne. Proteomics is a scientific endeavor that attempts to study the sum total of all of the proteins in a cell from the print of view of their individual functions and how the interaction of specific proteins with other cellular components affects the function of these proteins. Not surprisingly, this is a very complex task. There are many more proteins than there are genes, and in biochemical pathways, a protein The

rarely acts by itself. At present, we know that the expression if multiple genes is involved for any given disease process.

"Simply" knowing the gene sequence rarely unmasks the lanction of the encoded protein or its relevance to a disease. Csiniequently, the science of pmteomics is not developed to

he point at which drug discovery can be driven by gene sequence information. There have been, however, some sig-

technology-driven approaches to the field. Highthroughput high-resolution mass spectroscopy allows the amino acid sequences of proteins to be determined very quickly. The technique of two-dimensional gel electrophoresis has likewise advanced the science of proteomics. Protcoarcs will, undoubtedly, eventually provide targets for drug discovery and the detection of disease states.

193

positively (the desired outcome). or not at all. Consequently. drugs are developed for an "average" patient. The manufac-

turer relies on clinical studies to expose potential adverse reactions and publishes them in statistical format to guide the physician. Nevertheless, when a physician prescribes a drug to a patient he or she has no way of knowing the outcome. Statistics show clearly that a single drug does not provide a positive outcome in all patients. This 'one drug does not fit all" concept has its basis in the genetics of a patient. and the science of studying these phenomena is called phammacogenomics.

A patient's response to a drug, positive or negative, is a highly complex trait that may be influenced by the activities of many different genes. Absorption, distribution, metabolism. and excretion, as well as the receptor-binding relationship, are all under the control of proteins, lipids, and carbohydrates, which are in turn under the control ol the patient's genes. When the fact that a person's genes display small variations in their DNA bane content was recognized, genetic prediction of response to drugs or infectious microbes became pos.sible. Pharmacogenomics is the science that looks at the inherited variations in genes that dictate drug response and tries to define the ways in which these variations can be used to predict if a patient will have a positive response to a drug, an adverse one, or none at all. Cataloging the genetic variations is an important phase of present research activity. Scientists look for SNPs in a person's gene sequences. SNPs are viewed as markers for slight

genomic variation. Unfortunately, traditional gene sequencing is slow and expensive, preventing for now the general use of SNPs as diagnostic tools. DNA microarrays may make it possible to identify SNPs quickly in a patient's cells. SNP screening may help to determine a response to a drug before it is prescribed. Obviously, this would be a tremendous tool for the physician.

ANTISENSE TECHNOLOGY During the process of transcription, double-stranded DNA is separated into two strands by polymerases. These strands are named the sen.se (coding or + ) strand) and the anhisense (template or f—j strand). The antisense DNA strand serves as the template for mRNA synthesis in the cell. Hence, the code for ribosomal protein synthesis is normally transmitted

through the antisense strand. Sometimes, the sense DNA strand will code for a molecule of RNA. In this case, the resulting RNA molecule is called an:isen.se RNA. Antisense RNA sequences were first reported to be naturally occurring molecules in which endogenous strands formed complemen-

abet how individual patients will respond to the agent. No wnple algorithms exist that facilitate prediction of whether

tarily to cellular mRNA, resulting in the repression of gene expression. Hence, they may be natural control molecules, Rationally designed antisense oligonucleotide interactions occur when the base pairs of a synthetic. specifically designed antisense molecule align precisely with a series of bases in a target mRNA molecule. Antisense oligonucleotides may inhibit gene expression transiently by masking the ribosome-binding site on mRNA, blocking translation and thus preventing protein synthesis. or permanently by cross-linkage between the oligonucleo-

a patient will respond negatively (an adverse drug reaction).

tide and the mRNA. Most importantly, ribonuclease H

Pliamaacogenomks18m When pharmaceutical companies develop new drugs for any iisen disease state, they are limited by a lack of knowledge

194

Wits,,,, and Gisivid's lrahovk of Organic Medicinal and Pharn,ace,,:ical ('he,nis,rv

(RNase H) can recognize the DNA—RNA duplex (antisense DNA binding to mRNA). ora RNA—RNA duplex (antisense

RNA interacting with mRNA). disrupting the base pairing interactions and digesting the RNA portion of the double helix. Inhibition of gene expression occurs because the digested mRNA is no longer competent for translation and resulting protein synthesis. Amisense technology is beginning to be used to develop drugs that might be able to control disease by blocking the

genetic code, interfering with damaged or malfunctioning genes. Among the possible therapeutic antisense agents

AFTERWORD Clearly. biotechnology has become an integral part of pharmaceutical care. Pharmacists need to become comfortable with biotechnology and its language to deliver this kind of care to their patients. This chapter has tried to present an

overview of the major biotechnotogical arenas present in the year 2003. The field is advancing rapidly. and every pharmacist must stay current with the literature on hiotech' nology.

under investigation are agents for chronic myclogenous leu-

kemia. I-IIV infection and AIDS. cytomegalovirus retinitis in AIDS patients, and some intlammatory diseases.

GENE THERAPY Gene therapy arguably represents the ultimate application

of rDNA technology to the treatment of disease. There are two ways to envision gene therapy: (a) the replacement of a defective gene with a normal gene or (b) the addition of a gene whose product can help fight a disease such as a viral

infection or cancer. In the former case, replacement of a defective gene, an actual cure can be effected instead of just

treating the symptoms. For example, in cystic fibrosis, a defective gene has been clearly identified as the cause of the disease, It is possible that replacement of the defective

gene with a corrected one could produce a cure. Similar possibilities exist for other inherited genetic disorders such as insulin-dependent diabetes, growth hormone deficiency. hemophilia, and sickle cell anemia. The ability to transfer genes into other organisms has other important applications, including the heterologous production of recombinant proteins (discussed above) and the development of animal models for the study of human diseases. Another area of exploration is the introduction of recombinant genes as biological response nioditiers. for example. in

preventing rejection following organ transplantation. If genes encoding host major histocompatibility complexes could be introduced into transplanted cells, the transplanted tissue might be recognized as "self." It might also be possible to introduce genes for substances such as transforming growth factor-a that would decrease local cell-ntediated immune responses. An opposite strategy might be considered for the treatment of cancer. whereby transplanted cells could be used to target cancer cells, increasing local cell-mediated immune responses.

The transfer of genes frotn one organism to another is termed :ransgenics. and an animal that has received such a

transgene is referred to as a :ran.vgenic animal. If the transgene is incorporated into the germ cells (eggs and

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Ion, DC. ASM Press, 1998. Franks, F. led. I: Protein Biotechnology. Tonowa. NJ. 1-lumana Press.

56. Bains. W.: Biotechnology from A to '1,, 2nd ed Oxford. England, Oslord University Press. (998. 57. Alfwrls. B.. Bray. D.. Lou is. 3.. et al (eds.r Molecular Biology of tIre Cr11. 3rd ed New York. NY. Garland Publishing. 994. 59 SYolle. S. 1..: An Introduction to ('elI and Molecular Biolog>. Belnun. CA. SVadsworth Pnhlishing. 1995. 39. Williams. D. A.. and txmke. T. L. leds.t: Po>e's Principles olMedici-

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Wiles A Sons. 1995. PIt 944..945. liltirsun. SI F.. and Kaltti, M.: In Pet.onto. S. SI.. Joliiison. P4. 0., .ini Xl.irasse, H. K. leds.). Biirtechnolrigy and Phanti.mcy Ness York.

114. Zsebs,. K. P4. Cmulienm. A. P4.. et al.: Inirrounohiolmngv 72:175— 84. 1986.

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115. Suruoa. L

2(3—224. 1986. 113. Eschenhach. 3. W., en al.: Ann Intern. Mcml. 111:992—1(881. (989.

I)nsure. 'I'. C., ci at: Science 232:61—65. (986.

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116. Heil. G., Hoclzcr, ft. ci ul.: Blood 90:471(1—4718. 1997. Ill. Metcalf. D.: Blood (,7(21:257—267, 191(6. ItS. Vadltan.Raj, S.. Kcating. M.. ci al.: N. lingl. J. Med. 317:1545—1552. 1987.

119. Facts and Compansons. St. Louis. MO. Facts and Comparisons, 200(1. pp. 192—194.

120. Grabensicin. 1. ft led.): lmmunoIacLc: Vaccines and Immunologic Drugs. St. Louis. MO, Facts and Comparisons. 2(812. pp. 695—704. 121. Pegasys. Roche Pharmaceuticals Company Stal/Gram. Nutley. NJ, HoFfman-LaRoche, 2003. 122. Giabenstein, J. D. led.): Immunolacts: Vaccines and Immunologic Drugs, St. Louis. MO. Facts and Comparisons. 2002, pp. 705—717. 123. Grabcnsiein. J. D. led.): Immunolucis: Vaccines and Immunologic I)rugs. Si. Louis, MO, Facts and Comparisons. 2002. pp. 737-740 and references therein, 124. Grabcnstein. 3. D. (ed.): Immunofacts: Vaccines and Immunologic Drugs. St. Louis. MO. Fads and Comparisons. 2(8)2. pp. 741—745 and references therein. (25. Grabensicin. J. D. led.): Immunofacts: Vaccines and Immunologic Drugs. St. Louis, MO. Pacts and Comparisons. 2(8)2. pp. 746—752 and references therein. 126. Grahensicin. .1. I). (Cd.): Immunofacts: Vaccines and Immunologic Drugs. St. Louis, MO, Facts and Comparisons, 2002. pp. 756-764 and references therein, 127. J. I). lcd.): Immunofacts: Vaccines and Immunologic Drugs, St. Louis. MO, Facts and Comparisons. 2002, pp. 765—770 and references therein. 128. Grabenstein. J. D. led.): linmunofacts: Vaccines and Immunologic Drugs. St. Louis. MO. Facts and Comparisons. 2002. pp. 771—775 and refercncc,s therein.

Vaccines and Immunologic (29. Grabenstcin, 3. 13. led.): Immunof.u, Drugs. S, Louis, MO. Facts and Comparisons. 2(1)2. pp. 776—787 and references therein. 130. Grabcn.stein. J. 0. (ed): Immunofucts: Vaccines and Inttnunologic Drugs. St. Louis, MO. Facts and Comparisons. 2002. pp. 788-794 and references therein. 131. Graben.ctein, J. D. led.): Immunofacts: Vaccines and Immunologic Drugs. St. Louis. MO, Facts and Comparisons. 2002. pp. 795—802 and references therein. 132. Murray. K. M.. atid DahI. S. I..: Ann. Phannacoiher. 31(11): .

1335—1338, 1997.

(33. Weinh}atl. M.. et al.: Arthritis Rhcum. 40(Suppfl:S 126. 1997. 34. Moreland. 1. W.. et ul.: N. EngI. J. Med. 337:141—147. (997. 135. Veriitraate. M., Lijnen. H.. and Cullen. 0.: Drugs 50(11:29—42. 1995. 136. Facts and Comparisons. St. Louis. MO. Facts and Comparisons. 2(100. pp. 183—11(9.

137. Cannon, C. P. Gibson, C. M., ci al.: Circulation 98:2805—2814. 1998. 138. Facts and Comparisons. Si. Louis. MO. Facts and Comparisons. 2000. p. 193. 139. Shapiro. A. D.. Ragni, M. V.. Lasher. J. M.. em al.: Throinh. Haemost. 75(11:30—35. 1996.

140. Facts andComparisons. St. Louis. MO. Facts and Comparisons. 20(8), p. 195. 141. Bernard, G. R.. et al.: N. EngI, J. Med. 344:699—709. 2001. 142. Fabrialo. M.: J. Am. Soc. Extra Corporeal Tech. 331:117—125.2001. 143. Facts andComparisons. S.. Louis, MO. Facts and Comparisons. 2000. pp. 679—680. 144. Facts and Comparisons. St. Louis. MO. Facts and Comparisons. 2000. pp. 355.

145. Facts and Comparisons. St. Louis. MO. Facts and Comparisons. 2000. pp. 1529—1531. 146. Facts and ('oniparisons. St. Louis. MO. Facts and Comparisons. 2000. pp. 1505—1508. 147. Reichmamin. L., et at.: Nature 332:323—327. 1983. (48. Cohhold. S. P., and Wuldmuann, H. Nature 334:460—462. (984.

149. Muir,). K.. etal.. In Cromtnrlin, 0. J. A.. and Sindelar, R. 0. led.'.). Pharmaceutical Biotechnology: An Introduction for Pharmacists and Pharmaceutical Scientists. Amsterdam. The Netherlands. Harwood Acadentic Publishers. 1997, pp. 279—287. 151). CoiIfier. It.. et at.: N. Engl. J. Med. 346(4):280—282. 2002. 151. Maloney. D. G., ci al.: Blood 90:2188—2195. 1997. 152. Grabenstein. 3. D. (cdl: IntmunofacLs: Vaccines and ltttimtunotogic Drugs, St. Louis. MO. Facts and Comparisons, 2(8)2, pp. 44)6413 and references therein

IS). Voliotis, D.. ci ul.: Anti. Oncol. 11(41:95-100, 2000. 154. Grubenstein. 3. 0. (edt: Inimnumiofucts: Vaccines and Inmmnumiokigic Drugs. St. Louis, MO. Facts and Comparisons, 2(8)?. pp. 414—422 and rrlcrences therein.

55. McConnell. H.: Blood 00:768—773, 2002. 156. Billaud. E. M.; Therapie 55)11:177—183. 2000. 157. Ponticelli. C'., ci al.: Drugs l(1t55—60. 199'). 158. Kirkman. R. L.: Transplant. Proc. 31(1-21:1234— 1235. (999. 159. Vincenti, P.: N. Engi. 3. Mcd. 338: 101—165. (998. 160. Oberlmolzer. 3.. et at.: Transplant, lot. 14(21:169—171. 2188).

161. Chan, G. L. C., Grubcr. S. A., ci al.: ('nt. Care Clin. 6:841—892. 1990.

162. Hooks. M. A.. Wade. C. S., and Milliken, W. 3.: Pliarniacotlmrrap) 11:26—37. 1991.

63. Todd. P. A.. and Brogden. K. N.: I)rugi. 37:871—89'). 1989. (64. Tnpol, Ii. 3.. and Semsys. P. W.: Circulation 98:1802-1820. 1994. (65. Grabenstein. J. 0. led.): IntmuniiIaas: Vaccines and Imntunolugk Drugs. St. Louis. MO. Facts and Contparisons. 2(8)2, PP 455—462 and relcrencc.s therein. 166. Gelmon. K., Arnold, A.. Cl al.: Proc. Am. Soc. Clin. Oncol. 2t'l(69a1 Absrr. 271. 200). 167. Slumomi, D. J.. Lcyland—Jones. B.. ci al.: N. EngI. J. Med. 3444111 783—792. 200(1,

168. (irubenstcin, J. D. (ed): Immunofacts: Vaccines and Inimitunotogir Drugs. St. Louis. MO, Facts and Comparisons. 2(8)2. pp. 473-442 and references therein.

(69. Hanauer. S. B.: N. Engi. 3. Mcd. 334:84 I, 1996. 171). Bngunl, W. C.. Jr., et al.: Semin. Noel. Med. 19(31:202—22(1. 1919 171. A. I.: J. Noel. Mcd. 32191:1751—1753. 1991. 1991. 172. Reilly. K. M.: Ctin. Pttarmactml. 'I'her. 173, Reilly, K. M.. ci al.: Clin. Pharntacokinei. 24:126—142. 1995. 174. Grabenstein. 3. 13. (ed): Itnmunofacts: Vaccines and Imntunologv Drugs. St. Louis. MO. Fads amid Compansons. 2(8)2. pp. 535-54! and references therein. 75. Grahensiein. J. D. led.): Immunofacis: Vaccines and Immunmilogs Drugs. Si. Louis. MO. Facts and Comparisons, 21112. pp. 544-554 and references therein. 176. Quailroccltl. E., and Hove, I. 1.IS Plrann. 23(41:54—63, 1998. 177. Riot, M.: Pharm. Tech. 25(l):34—40. 2000. 178. Ramsey. Ci.: Nat. Biotcch. 16:40—44. 1998. 179. Khan. 3.. ci al: Biochim. Biophys. Acts 1423:17—28. 1999. 180. Persidis. A.: Nat. Biotech. 16:393—394, 1998. 181. Borman, S.: Chem. Eng. News 78:31—37, 2000. 182. Lau. K. F., and Sakul. H.: Annu. Rep. Med. Chetit. 36:261—269.21(4),

CHAPTER 7 Immunobiologicals ORN M BEALE, JR.

immune system constitutes the body's defense against It protects the host by identifying and elimsating or neutralizing agents that are recognized as nonscif. liv entire r.tnge of immunological responses affects essenicIly organ, tissue, and cell of the body. Immune re-

include, in part, antibody (Ab) production, allergy. stiatnination, phagocytosis. cytotoxicity. transplant and rejection, and the many signals thai regulate these At its most basic, the human immune system he described in tcnns of the cells that compose it. Every r'pcct of the immune system. whether innate and nonspea set of specialThus, this discussion of some of the fundamentals immunology begins with the cells of the immune system.

MHCs con be found on virtually all nucleated cells in the human body, while class II MHC molecules are associated only with B lymphocytes and macrophages. Class I MHCs are markers that are recognized by natural killer cells and cytotoxic T lymphocytes. When a class I MHC is coexpressed with viral antigens on virus-infected cells. cytotoxic target cells are signaled. Class II MHC molecules are markers indicating that a cooperative immune slate exists between immunocompetent cells, such as between on antigen-presenting cell and a T-helper cell during the induction of Ab formation.

Granulocytes4 If one views a granulocyte under a microscope, one can observe dense intracymoplasmic granules. The granules contain inflammatory mediators and digestive enzymes that de-

CELLS OF THE IMMUNE SYSTEM

stroy invading pathogens. coiitrol the rate and pathsvay of migration of chentotactic cells, and cause dilation of blood

All immune cells derive from pluripolent stem cells in the hoix marrow. These arc cells that can differentiate into any slier cell type, given the right kind of stimulus (Scheme 7Ii A satiety of modes of differentiation beyond the stein ctll give rise to unique cellular types, each with a specific in the immune system. The first stage of differentia1ises rise to two intermediate types of stem cells and it branch point.a These cells are the myeloid cells snyeloid lineage) and the lymphoid cells (lymphoid line-

vessels at the infected site. The increased blood tiow ensures that an ample supply of granulocytes and inflamnniatory me-

diators reaches the site of infection. There is a t'amily of granulocytic cells, each member with its own specialized function. Under microscopic examination. some granulocytes are seen to be multinuclear and some mononuclear. The configuration of the nuclear region and the staining behavior provide ways of classifying granulocytes. The group is discussed below,

.cem. Carrying the lineage further leads to additional branch-

The myeloid cells differentiate into erythrocytes and also monocyes and granulocytes. The

rIjirlets and

limphoid cell differentiates into B cells and T cells, the cells th.d ,ur am the center of adaptive immunity. The switching

or each pathway and cell type is governed by a tummher of colony-stimulating factors, stein cell flictors. and rierleukins, These control proliferation, differentiation, and scluratiott of the cells.

Major Histocompatiblilty Antigens—Self

NeubophOs' Nen:rup/mits' arc the primary innate defense against pathogenic bacteria. They make up most (50(075%) of the kukocyte fraction in the blood. Microscopically. neutrophils have multilobed nuclei. They respond to chemical motility factors such as complement mediators released from infected or inflamed tissues and migrate to a site of infection by the process of chemotaxis. There, they recognize, adhere to. and phagocytose invading microbes.

Venus Nonseif The development of most immune responses depends on hr

of what is self and what is no: se/f. This must he clear and must be done in a very

:ercral way. This recognition is achieved by the expression i specialiced surface markers on human cells. The major

soup of markers involved in this recognition consists of 'urfare proteins. These ore referred to as the major hiswcom-

cmnpler3 (MHC) or major liiswco,nparibilizv anti. Proteins expressed on the cell surfaces are class I class Il MHCs. Both classes are highly polymorrhic antI so axe highly specific to each individual. Class I

Phagocytes The phagocytic process is initiated by contact and adhesion of an invading cell with a phagocytc cell membrane. Adhesion triggers a process whereby the phagocytic cell extrudes pseudopodia that surround the adhering tnicrobe. As this process progresses, the microbe is actually surrounded by

the phagocyte cell membrane. Then. invagination of the membrane fully engulfs the particle, and the membrane is resealed, with the particle encased inside an intracellular vacuolar body called a phugosome. Lysosomes in the cyto-

plasm then fuse with the phagosome to form plwgolvso197

198

Wil.s,,,, and Gi.ssolds

of Orcrwth Med icina! and Pharrnaceuiieal ('heniisrn

Lymphocytes Cells

Natural KIller Cell Scheme 7—1 • Lineages of blood cells. All blood cells derive from a pluripotent stem cell. A variety of cytokines direct the cells into their specific populations

conies. The antimicrobial compounds in the phagosomes and

lysosornes kill the engulfed pathogen and enzymatically cleave its remains into smaller pieces.

Eoslnophlls5 Eosinophils are granulocytes that can function as phagocytes. but much less efliciently than neutrophils can. They ate present as 2 to 4% of blood leukocytes. Their name derives from the intense staining reaction of their intracellular granules with the dye eosin. Eosinophil granules contain

(IgE) receptors. Complexes ot antigen molecules with IgE receptors ott the cell surface lead to cross-linking of IgE and distortion of the cell membrane. The distort ion causes the mast cell to degranulate. releasing mediators of the allergic response. Because of its association with hypersensitivity. IgE has been called "reogin" in the allergy literature. Diagnostically. lgE levels are elevated in allergy. systemic erythematosus. and rheumatoid arthritis. Cronsolyn sodium is a drug that prevents mast cell degranulation and thus blocks the allergic response. Cromolyn is used in asthma.

inflammatory mediators such as histamine and leukotrienes.

so it makes sense that these cells are associated with the allergic response. Clues to the functions of eosinophils come

front their behavior in certain disease slates. Eosinophil counts are elevated above normal in the tissues in many different diseases, hut they are recognized primarily for their diagnostic role in parasitic infections and in a unique mode of action that lends to their extreme importance. Unlike neutrophils. eosinophils need not phagocytose a parasite to kill it. Indeed, some parasites are too large to allow phagocytosis. Eosinophils can physically

surround a large parasite. forming a cell coat around the invader. Eosinophil granules release oxidative substances capable of destroying even large. multicellular parasites. Hence, even when phagocytosis fails, a mechanism exists to destroy large parasites.

Mast Cells and Basophils

Macrophages and Monocytes4'5 Macrophages and monocyle.s are mononuclear cells that axe capable of phagocytosis. In addition to their phugocytic capabilities, they biosynthesiz.e and release soluble factors (complement. monokines) that govern the acquired immune response. The half-life of monocytes in the bloodstream about 10 hours, during which time they migrate into tissues and differentiate into macrophages. A macrophage is a terminally differentiated monocyte. Macrophages possess a true anatomical distribution because they develop in the tissues to have specialized functions. Special macrophages are found in tissues such as the liver, lungs, spleen. ga.strointesu. nal (Gil tract, lymph nodes, and brain. These specific macrophages are called either histiocvtes (generic term) or by tam specialized names (Kupffer cells in liver. Langerhwii cells in skin. ah'eo!ar ,nacrophuges in lung) tlable 7—I ). Thr

Mast cells and basophils also release the inflammatory mediators commonly associated with allergy. Mast cells are especially prevalent in the skin, lungs. and nasal mucosa: their granules contain histamine. Basophils. present at only

entire macrophage network is called the re;iculoe,:doiheliu sr.cten,. Other macrophages exist tree in the tissues. where they carry out more nonspecific functions. Macrophages kill more slowly thati neutrophils but have a much broader slrec. trum. It has been estimated that more than 1(X) soluble in

0.2% of the leukocyte fraction in the blood, also contain

tiammatory substances are produced by macrophages. These

histamine granules, but the basophile.s found circulating in the blood and not isolated in connective tissue. Both mast

substances account for macrophages' prolific abilities to di. rect. modulate, stimulate, and retard the immune response. Macrophages possess a very specialized function: they

cells and basophils have high-affinity immunoglobulin E

Chapter 7 U Inimunobiologicals

TAELE 7—i

Reticutoendothellal System Cell

Tissue Kupflcr orlLs

L.wer

Alveolar mocrophages (dust cells)

199

act as antigen-presenting cells (APCs) (Fig. 7-I). APCs are responsible for the preprocessing of antigens, amplifying the numbers of antigenic determinant units and presenting these determinant stnictures to the programming cells of the immune system. APCs internalize an organism or particle and digest II into small fragments still recognizable as antigen. The fragments are conjugated with molecules of the major

Poritoneal inacrophages

histocompatibility complex 2 (MHC-ll). These complexes

Spleen

Dcndritic eclis

5km

l,anguihuns cells

Ilialo

Microgliul cells

are responsible for self or nonself cell recognition and ascertain that cells being processed are not self. MHCs also direct the binding of the antigenic determinant with immunoreac-

tive cells. Once the antigen—MHC-IT complex forms, it undergoes transcytosis to the macrophage's cell surface. where B lymphocytes and helper T cells recognize the anti-

Antigen

1-Helper Cell

/

Clones of functionally silent memory B cells

N Antibody-producing plasma cells

—
e int'eciitm .cnccptuui itis

Inactivated sorts Icilleacy uncennint

!udr. arri-A

Herpes sinipler 2

Genital herpes, skirt eruptions

None

Varieella ,.ostcr

Chackenpox (children). shingles (adrilla)

None

Acvelovir Acyctovir

C> tonrcgainvirua

trifeetiims in tIre iiirnnrnruiirirproinised.

None

Oancictosir.

None

None

Nitric

Podophyltin

herpes samples

I

fescarneu

neonates

Epstein-Barr siau.s

Inlecticru'. moirrinu eosir, Burkitt's

lymplionu Papovccvinca

t'cpilltrmasirus

\Varts

Polyrmasirus (IC vicrist

Pargeessive leukoetceeplicrlopathy

None

Adeciovinis Human adenovinas

Upper respiratirry tract and eye nieciioris

Nitric

None

Hcpalilis (rim> Decatur chorale)

tncrctivcitcd subunit (scry

None

Hepadcrasiru'.

Hepatitis B virus

eflettive) Pi,xvincs Varcola

Sticailpon

Vuednia Ieowtxrxi (very etiectice)

Methiscaircie

t(iytlrcma, tterncrlytic anemia

Noire

None

I'arvor lots Iticrucir trarx'osirun 1311)

induce an eft'ective antibody response. even in very young patients: the vaccine must not cause the disease that it is designed to prevent or cause some other toxic manifestation as the early killed vaccines did: and ideally, the vaccine should produce a

lasting form of immunity, with a minimum requirement for booster doses. These requirements are difficult enough to meet for viruses that cause acute untections. The chronic cases are much more complicated. It is difficult to overcome

the tendency of some viruses to undergo rapid mutation. leading to multiple antigenic epitopes: this makes development of a broadly effective vaccine much more difficult.

Biochemical Targets for Antiviral Therapy With the discovery ol antibiotics and anti-infective agents, the science of treating bacterial infections moved forward at a rapid rate. The development of useful antiviral agents (antibiotics and antiviral agents. in contrast, has historically Unlike lagged behind. There are a number of reasons for bacteria. viruses will not grow in simple synthetic culttire media. They must infect human or animal cells to propagate.5 For example. the most commonly used cell cultures

in virology derive from priniates (including humans and monkeys). rodents (including hamsters and mice), and birds (especially chickens). These culture methods are very reliaand are in widespread use the propagation of virus

particles. hut they are more difficult to perform than their bacterial counterparts. Hence, drug-screening techniques with viruses have taken longer to catch up with those in

bacteria. Another possible reason for the lag in development lies in the comparative biochemical simplicity of viruses vis-à-vis bacteria and their use of the biochctaicrl processes of a host cell. There are fewer specialized for potential attack by chemotherapeutic agents. The spectacular successes of immunization procedures ho I): prevention of certain viral diseases may have contributed I a relative lack of interest in antiviral chemotherapy. Anolirt feature of mild viral infections, such as the common cnh[ is that clinical symptoms do not appear until the iniectio3 is well established and the intmune processes of the its have begun to mount a successful challenge. Thus, formats common viral infections, chemotherapy is simply not prolar ate choice of treatment. Chemotherapeutic agertis clv needed, however, to combat viruses that cause severe r chronic infections, such as encephalitis. AIDS. and lieqv particularly in patients with compromised immune

THE INFECTIOUS PROCESS FOR A VIRUS Despite their simplicity relative to bacteria, viruses still sess a variety of biochemical targets for potential attack chemotherapeutic agents. An appropriate chemical ocr pound may interrupt each of these. Hence, a thorough standing of the specific biochemical events that occurdanny

viral infection of the host cell should guide the site-specific antiviral agents. The process of viral infcoot can be sequenced in seven stages:

Chapter II • Antiviral Agents attachment7 of the virus to specific receptors on the surface of the host cells, a specific recognition process.

I

2

Enu-i. penetration7 of the virus into the cdl.

o viral nucleic acid from the protein coat. Trwiscr,ption. production of viral inRNA from the viral ge-

3. Unroarin,n. release7 4

tame.8

Translation. synthesis8 of' viral proteins (coat protcins and en-

cynics for replication) and viral nucleic acid (i.e.. the parental genome or complimentaiy strand). This proces.c uses the host cell processes to express viral genes, resulting in a few or many viral proteins involved in tile replication process. The viral proteins modify the host cell and allow the viral genome to replicate

371

with a cyfokine

Substantial evidence indicates that viruses enter cells by endoevw.cis. a process that involves fusion of the viral envelope with the cell membrane.

intermixing of components, and dissolution of the menibranes of virus and cell. Various receptors and coreceptors facilitate this reaction.'7 Before a virus can begin a replication cycle within a host cell, its outer envelope and capsid must be retnoved to release its nucleic acid genome. For complex DNA viruses such as vaccinia (its binding receptor is the epidermal growth factor receptor), the uncoating process occurs in two

by using host and viral enzymes. The mechanisms by which his occurs are complex. This is often the stage at which the is irreversibly modified and eventually killed, ts Assembh' of the viral particle. New viral coat proteins assemble inti, capsids (the protein envelope that surrounds nucleic acid and associated molecules in the core) and viral genomes.8 Release of the mature virus from the cell by budding from the cell membrane or rupture of the cell and repeat of the process. 1mm cell to cell or individual to individual.8 Enveloped viruses typically tise budding on the plasma membrane. endoplasmic reticulutn. or Golgi membranes. Noneitveloped viruses typically ecapc by rupture of the host cell.

stagest 1:

The initial attachment of viral particles to cells probably imolves multiphasic interactions between viral attachment and host cell surface receptors. For instance, in the case of the alphaherpesviruses, internalization involves of events that involve different glycoproteins and cell surface molecules at different stages. Different surtitce proteins may be used for the initial attachment .isi entry into target cells and for cell-to-cell spread across apposed populations of cells.5 The pattern of systemic illness produced during an acute viral infection in large part &pends on the specific organs infected and in many cases in the capacity of the viruses to infect discrete populations 1 cells within these organs. This property is called tissue The tissue tropism of a virus is influenced by interaction between a variety of host and viral factors. Although the specific viral aftachmenr proteins and spe-

hut they are not selective enough to be useful us antiviral

ofic receptors on target cells are important, a variety of virus—host interactions can play an important role in the tropism of a virus. Increasing attention is king focused on corceeptors in mcdiatitig viral binding. Instance, entry of HIV-l into target cells requires the of both CD4 and a second coreceptor protein to the G-protein--coupled seven-transmembranc

fatally. including the chemokine receptor proteins CCRS and CXCR4. Cells that express CD4 but not the cisceeptor are resistant to HIV infection. Host cellular recep-

Is can he integrins. hcparans. sialic acids. gangliosides. phospholipid.s. and major histocompatibility anti(to name a few). There is substantial evidence that tile receptor for influenza viruses is the pcptidogiycan sanpenent N-acctylmuramic acid, which binds a protein hemagglutinin. projecting from the viral surface.t2 ite binding of N-acetylmurarnic acid and hemagglutinin in motion a sequence of events whereby the viral envethe host cell membrane dissolve into each other, and issiral contents enter the cell. Initiation of HIV- I infection solves the interaction of specific glycoprotein molecules

that stud the viral cell surface with an untigenic receptor molecule on helper T lymphocytes along

I. I-lost cell enzymes partially degrade the envelope and eapsid to reveal a portion of the viral DNA. which serves as a template for mRNA synthesis. 2. mRNAs code for the synthesis of viral enzymes. which complete

the degradation of the protein coat, allowing the virus to fully enter the host.

The proteins of the viral envelope and capsule are the primary targets for antibodies synthesized in response to immunization techniques. Protein synthesis inhibitors such as cyclohexinnide and purotnycin inhibit the uncoating process. agents.

In the critical fourth and liITh stages of infection, the virus usurps the energy-producing and synthetic functions of the host cell to replicate its own genome and to synthesize viral enzymes and structural proteins.-0 Simple RNA viruses conduct both replication and protein synthesis in the cytoplasm of the host cell. These contain specific RNA polymera.scs (RNA replicases) responsible for replication of the genonle. Some single-stranded RNA viruses, such as poliovirus. have a ( + )-RNA genome that serves the dual function of messenger for protein synthesis and template for the synthesis of a complementary strand of (—)-RNA. from which the (+ )RNA is replicated. In poliovirus (a picornavirus). the message is translated as a single large open reading frame whose product is cleaved enzymatically into specific viral enzymes and structural proteins)8' Other RNA viruses, such as influenza viruses, contain (—)-RNA. which serves as the tem-

plate for the synthesis of a complementary strand of N- )KNA. The (+ )-RNA strand directs viral protein synthesis and provides the template for the replication of the (—)-RNA genome. Certain antibiotics, such as the rifamycins, inhibit

viral RNA polynacrases in vitro, but none has yet proved clinically useful. Bioactivated forms of the nuckoside analogue ribavirin variously inhibit ribonucleotide synthesis. RNA synthesis. or RNA capping in RNA viruses. Rihavirin has been approved for aerosol treatment of severe lower respiratory infections caused by respiratory syncytial virus (RSV).

Retroviruses constitute a special class of RNA viruses that posses.s a RNA-dependent DNA polymerase (relerse transcripta.ve) required for viral replication. In these viruses. a single strand of complementary DNA (eDNA) is synthesized on the RNA genome (reverse :ran.vcriplion). duplica. ted, and circularized to a double-stranded proviral DNA. The proviral DNA is then integrated into the host cell chromo-

somal DNA to form the template (upovirus or virogene) required for the synthesis of mRNAs and replication of the viral RNA genome. During the process of eDNA biosyn-

372

of Organic

and Gi.cvold's

degrades the RNA strand, leaving only a DNA. Oncogenic (cancer-causing) viruses, such as the

Late stages in viral replication require important virus. specific processing of certain viral proteins by viral orcellu'

human 1-cell leukemia viruses (HTLV) and the related HIV. are retroviruses. Retroviral reverse tr.Iuscriptase is a good target for chemotherapy. being inhibited by the triphosphates of certain dideoxynucleosides. such us 2'.3'-deoxy-3'-

lar proteases. Retroviruses, such as HIV. express three genes as precursor polyproteins. Two of these gene products. designated the p55gag and p1 6Ogag-pol proteins for their Irea' tion on the genome. undergo cleavage at several sites by a virally encoded protease to form structural (viral coat) proteins (p17. p24, p8. and p7) and enzymes required for repli. cation (reverse transcriptase. integrase, and protease). The demonstration that HIV protease. a member of the aspunyl protease family of enzymes, is essential for the maturation

azidothymidine (AZT. zidovudine). 2'.3'-dideoxycytidine (ddCyd. zalcitahinc). and 2'.3'-dideoxy-2'.3'-didehydrothymidine (D4T. stavudine). all of which have been approved for the treatment of AIDS. The nomenclature of these

agents is straightforward. A 2'.3'-dideoxynucleoside is referred to as ddX. while the unsaturated 2'.3'-dideoxy-2'.3'didehydrunucleosides are named d4X. The dideoxynucleoside triphosphates arc incorporated into viral DNA in place of the corresponding 2'.deoxynucleoside (i.e.. 2'-deoxythymidine. 2'-deoxycytidine. or 2'.deoxyadenosine) triphosphate.22' This reaction terminates the viral DNA chain. since the incorporated dideoxynucleoside lacks the 3'-hydroxyl group rcqttired to form a 3'.5'-phosphodiester bond with the next 2'-deoxynucleotide triphosphate to be incorporated. The DNA viruses constitute a heterogeneous group whose genome is composed of DNA. They replicate in the nucleus of a host cell. Some al the DNA viruses are simple structures. consisting of a single DNA strand and a few enzymes surrounded by a capsule (e.g.. parvovirus) or a lipoprotein envelope (e.g.. hepatitis B virus). Others, such as the hcrpesvi-

and infectivity of HIV particles24 has stimulated major search efforts to develop effective inhibitors of this step. These efforts have led to several candidates, some that ate

on the market and many that are in clinical trials. To complete the replication cycle, the viral are assembled into the mature viral particle, or virion.

Fat

simple. nonenveloped viruses (e.g.. the picornavirus poliovi' rus). the genome and only a few enzymes are encased by capsid proteins tO complete the virion. Other, more comples viruses arc enveloped by one or more membranes containiny carbohydrate and lipoprotein components derived front the host cell membrane. Once the mature virion has been assembled, it is ready for release from the cell. The release of certain viruses (e.g.

roses and poxviruses. are large, complex structures with double-stranded DNA genonies and several enzymes en-

poliovirus) is accompanied by lysis of the host cell

cased in a capsule and surrounded by an envelope consisting

ever, are released by budding or exocvta.si.s. a process involv. ing fusion between the viral envelope and the cell membrane

of several membranes. l)NA viruses contain DNA-dependent RNA polymerases (IraItscripta.ces), DNA polymerases. and various other enzymes (depending on the complexity of the virus) that may provide targets for antiviral drugs. The most successful chernotherapeutic agents discovered thus far are directed against replication of herpesviruses. The nucleo-

side analogues idoxuridine. iritluridine. and vidarabine block replication in herpesviruses by three general mechanisms: First, as the monophosphates. they interfere with the biosynthesis of precursor nucleotides required for DNA synthesis: second, as Iriphosphates. they competitively inhibit DNA polyrnerase: and third, the triphosphates are incorpo-

rated into the growing DNA itself, resulting in DNA that is brittle and does not function normally. Acyclonucleosides (e.g., acycloguanosine) are bioactivated sequentially by viral and host cell kinases to the acyclonucleotide monophosphate and the acyclonucleoside triphosphame. respectively. The lat-

ter inhibits viral DNA polytnerase and terminates the viral DNA strand, since no 3'-hydroxyl group is available for the subsequent formation of a 3',S'-phosphodiester bond with the next nucleoside triphosphate. The structure of acyclovir with the acyclosugar chain rotated into a pentose configuration (below) shows clearly the absence of the 3'-hydroxyl group.

0

H2N

N

brane and cell death. Some of the enveloped viruses, how'

This process is nearly a reversal of the entry process: the host cell membrane remains intact under these conditions and the cell may survive. Chemoprophylaxis is an alternative to active immuni?a• tion for the prevention of viral infection. With chetnoprophy laxis. one uses a chemical agent that interferes with a in early viral infectivity. The immune system is not diredy stimulated by the drug but i.s required to respond to any active infection. It would seem that the most successful moprophylactic agents would be those that prevent peneua•

(ion of the virus into the host cell. In principle, this can k achieved by blocking any of three steps prior to the start the replication cycle: (a) attachment of the virion to the hwi cell via its receptor complex. (h) its entry into the cell endocytosis. or (c) release of the viral nucleic acid front ih: protein Coat. At present, only a single class of agents these early stages of The adamantanaininn (arnantadine and ritliantadine) have been approved forcm

trolling influenza type A infection. These drugs appeat interfere with two stages of influenza type A viral replie tion: preventing the early stage of viral uncoating and turbing the late stage of viral assembly. Clinical studies ha: shown that amantadine and rimantadine are effective in prophylaxis and treatment of active influenza type A infe' tion. Amantadire, I Amantadine, USP, and Rimanta dine. adamantanamine hydrochloride (Symmetrel). and its

tnethyl derivative rimuncudine. thylamine hydrochloride Flumadine), are unusual cyclic amines with the following structures:

i

Chupter Ii • ,tIsIi%iral AgeIus

373

lo

NH2

against type A. The drugs on influenia type B. The primary side effects are related to the central nervous system and are dopami— nergie. This is not surprising, since amantadine is used in the treatment of l'arkinson's disease. Rimuntadine has significainthy kwer side probably because of its eXtetisive biotransformation. Less than 50% of a dose of rimantadine is excreted unchanged. and more than appears in the urine as tnelaholites.25 Amantadine is excreted largely unchanged in the urine.

have no

Amantadine

Rirnantadine

Aniantadine has been used for years as a lreattucrn for Parkinsons disease. Both of these agents will specilically

inhibit replication of the influen,a type A viruses at low concentrations. Ritnantadine is generally 4 to IC) limes more

than amaniadine. The adamantanamines have two mechanisms in common: (i,) they inhibit an early step in dial replication, most likely viral and (b) in sme slrains they affect a later step that probably itivolves viral assembly, possibly by with hemaggltutinin The main hiochetnical locus of action is the intype A virus M2 protein, which is an integral nienihrane protein that functions as an ion channel. The M2 chan-

is a proton transport systeni. By interfering with the unction of the M2 protein, the adamantanamities inhibit

nel

acid-mediated dissociation of the rihonucleoprotein coniplex carly in replication. They also interfere with transinetubrane pumping, maintaining a high intracellular proton conccntraljl)n relative to the cxtracellular concetliratioti and en—

tuncing acidic pH-induced conftrmational changes in the during its intracellular transport at a later ,wgc. The conformational changes in hemagglutinin prevent

of the nascent virus particles to the cell nienibranc or exocytosis.

Resistant variants of inlluen/a type A have been recovered (torn aniantadine- and riniantudine-treated patients. Resisunce with inhibitory concentrations increased more thatt have been associated ssith single tiucleotide

that lead to amino acid substitutions in ilte trailsdomain of M2. Amantadinc and rimantadine -tore cross-susceptibility and

\matitadine and rimantadine are approved in the United Stares tbr prevetition and treatment of inlluensa type A virus

Seasonal prophylaxis with either drug is about

INTERFERONS: INTERFERON ALFA (INTRON A, ROFERON A) AND INTERFERON BETA (BETASERON)

Interterons UFNs arc extremely potent cytokines that possess antiviral. innmtunotnodntlating. and anliproliferarive actiotisH lENs are synthesiied by infected cells in response

to various itiducers (Fig. Il-I) and, in turn, elicit either an antiviral state in neighboring cells or a natural killer cell respotise that destroys tile initially inlécted cell (Fig. 11-2). There are three classes of human IFNs that possess signilicant antiviral activity. These are IFN-a (more than 20 subtypes). subtypes), and IFN-y. IFN-a is used clinically in a recombinant fonn (called interferon alfa). (Betaseront is a recombinant form marketed for the treatnient of multiple sclerosis. IFN-a and arc produced by almost all cells in response to viral challenge. Interferon production is not limited to viral stimuli, however. A variety 01 other triggers, including cytokines such as interleukin-l. interleukin-2, and tumor necrosis factor, will the production of lFNs. Both IFNa and are elicited by exposure of a cell to doublestranded viral RNA. lEN-a is produced by lymphocytes and macruphages. while IFN-fJ is biosynthesited in flhrohlasts and epithelial cells. IFN-y production is restricted to T lyniphocytes and riatttral killer cells responding to anhigetnie stimuli. milogetta. and speeilie cyhokines. IFN-a and IFN-

fi hind to the same receptor, and the genes for both are encoded on chromosome 9. The receptor for INF-yis unique. and only one subtype has been identilied. The genes for this molecule are cimeoded on chromosome 12. INF-y has less antiviretl activity than IFN-co and but more potent

Type 1 Interferons

IFN-a

Type 2 Interferons IFN.y

IFN-f1

Lymphoblasts Macrophages

Fibroblasts, Epithelial Cells

Mrtogen.slimulated T Lymphocytes Induced by Mitogens or Lectlns

Induced by Double-stranded Viral RNA: Receptors identical

Receplor Unlike Type 1

Both encoded on Chromosome 9

Encoded on Chromosome 12

Figure 11—1 • Types of interferon

374

Wilson and Gi.wold's Textbook of Organic Medicinal and Pharmaceutical Chemistr-v

Activate by IFN

Killing

Infected Cell

Natural Killer Cell

Other Cells

FIgure 11—2 • Interferon mechanisms.

immunoregulatory effects. INF-y is especially effective in activating macrophages, stimulating cell membrane expression of class II major histocompatibility complexes (MHCII). and mediating the local inflammatory responses. Most animal viruses are sensitive to the antiviral actions of IFNs. The instances in which a virus is insensitive to IFN

typically involve DNA viruses)3 On binding to the appropriate cellular receptor, the IFNs induce the synthesis of a cascade of antiviral proteins that

contribute to viral resistance. The antiviral effects of the IFNs are mediated through inhibition of ° • Viral penetration or uncoating • Synthesis of mRNA • The translation of viral proteins • Viral assembly and release

With most viruses, the lFNs predominantly inhibit protein synthesis. This takes place through the intermediacy of IFN.

4— IFN Receptor

Induction of antiviral proteIn synthesis

2'5-Otlgoadenylate synthetase ATP

Ribonuctease R Hydrolyze Viral RNA

Figure 11—3 • lFNs predominantly inhibit protein synthesi5.

Chapter II •

Age,,ts

375

NH2

N

HN N H H

'H

Figure 11—4 • Structure of 2'.5'-oligoadenylate.

induced proteins such as 2',5'-oligoadenylate (2'.5'-OA) syn-

C. chronic hepatitis B. Kaposi's sarcoma in HI V-infected

thetases (Fig. 11-3) and a protein kinase. either of which inhibit viral protein synthesis in the presence of double-

patients, other malignancies, and multiple sclerosis.

aranded RNA. 2',S'-OA activates a cellular endoribo(RNase) (Fig. 11-4) that cleaves both cellular and

nuclease

viral RNA. The protein kinase selectively phosphorylates aal inactivates eukaryotic initiation factor 2 (eIF2). preventing initiation of the mRNA—ribosome complex. IFN also isiuces a specific phosphodiesterase that cleaves a portion c4 tRNA molecules and, thereby, interferes with peptide :Iongation.3° The infection sequence for a given virus may inhibited at one or several steps. The principal inhibitory urrrctdiffers among virus families. Certain viruses can block pmduction or activity of selected IFN-inducible proteins

NUCLEOSIDE ANTIMETABOLITES

Inhibitors of DNA Polymerase Idoxuridine,

USP. Idoxuridinc. 5-iodo-2'-deoxyuridine (Stuxil. Herplex), was introduced in 1963 for the treatment of herpes simplex keratitis.32 The drug is an iodinated analogue of thymidine that inhibits replication of a number of DNA viruses in vitro. The susceptible viruses include ihe herpesviruses and poxviruses (vaccinia).

0

.nd thus counter the IFN effect. IFNs cannot be absorbed orally: to be used therapeutically

must be given intramuscularly or subcutaneously. The effects are quite long, so pharmacokinetic paramare difficult to determine. The antiviral state in periph. .ial blood mononuclear cells typically peaks 24 hours after then decreases to baseline in 6 of IFN-a and Both recombinant and natural INF-a and INF-/'J are .çproved for use in the United States for the treatment of cnndytomu acuminatum (venereal warts), chronic hepatitis

HO'

Idoxuridine

376

of Organic Medicinal and Pharmaceutical Chemistry

Wilson and Gi.c;vld's

The mechanism of action of idoxuridine has not been completely defined, but several steps arc involved in the activation of the drug. Idoxuridine enters the cell and is phosphoryluted

at 0-5 by a viral thymidylate kinase to yield a

monc)phosphate. which undergoes further biotransformation to a triphosph'ate. The triphosphate is believed to be both a substrate and an inhibitor of viral DNA polymerase. causing inhibition of viral DNA synthesis and facilitating the synthe-

sis of DNA that contains the iodinated pyrimidine. The al-

Trifluridine is approved in the United States for the treatment of primary keratoconjunctivitis and recurrent epithelini kcratitis due to HSV types I and 2. Topical trifluridine shows some efficacy in patients with acyclovir-resistant HSV cutaneous infections. Trifluridine solutions are heat sensitive and require refrigeration.

Vidarabine, USP.

tered DNA is more susceptible to strand breakage and leads

to faulty transcription. When the iodinated DNA is transcribed, the results are miscoding errors in RNA and faulty protein synthesis. The ability of idoxuridylic acid to substitute for deoxythymidylic acid in the synthesis of DNA may be due to the similar van der Waals radii of iodine (2.ISA) and the thymidine methyl group (2.OOA). In the United States. idoxuridine is approved only for the topical treatment of herpes simplex virus (HSV) keratitis. although outside the United States a solution of idoxuridine in dimethyl sulfoxide is available for the treatment of herpes labialis. genitalis. and zoster. The use of idoxuridine is lintited because the drug lacks selectivity; low. suhtherapeutic concentrations inhibit the growth of uninfccted host cells. The effective concentration of idoxuridine is at least 10 times greater than that of acyclovir. Idoxuridine occurs as a pale yellow, crystalline solid that is soluble in water and alcohol but poorly soluble in most organic solvents. The compound is a weak acid, with a pKA of 8.25. Aqueous solutions are slightly acidic, yielding a pH

of about 6.0. Idoxuridine is light and heat sensitive, It

Chemically. vidarabine (Vira-A). is The drug is the 2' epimer

of natural adenosine. Introduced in 1960 as a candidate cancer agent. vidarabine was found to have broad-spectrum activity against DNA viruses.34 The drug is active against herpesviruses, poxviruses. rhabdoviruses. hepadnavirus. and some RNA tumor viruses. Vidarahine was marketed in thc

United States in 1977 as an alternative to idoxuridine fur the treatment of HSV kerutitis and HSV encephalitis. Al. though the agent was initially prepared chemically, it is mm obtained by fermentation with strains of St reptoin vet's anti I,jtn'ic'us. NH2

is

supplied as a 0.1% ophthalmic solution and a 0.5% ophthalmic ointment. USP. Trifluridine, 5-trifluoromethyl-2'dcoxyuridine (Viroptic), is a fluorinated pyrintidine nucleoside that demonstrates in vitro inhibitory activity against HSV I and 2. CMV. vaccinia. and some adenoviruses.33 Trifluridine possesses a trifluoromcthyl group instead of an iodine atom at the 5 position of the pyrimidine ring. The van der Waals radius of the trifluoromethyl group is 2.44A. somewhat larger than that of the iodine atom. Like idoxuridine. the antiviral mechanism of trifiurkilne

Trifiuridine,

involves inhibition of viral DNA synthesis. Trifluridine monophosphate is an irreversible inhibitor of thymidylate synthetase. and the biologically generated lriphosphatc com-

petitively inhibits thymidine triphosphate incorporation into

DNA by DNA polymerase. In addition. triflundine in its triphosphate form is incorporated into viral and cellular DNA. creating fragile, poorly functioning DNA.

0 CF3

Vidarabine

The antiviral action of vidarabine is completely confined

to DNA viruses. Vidarabinc inhibits viral DNA synthesis Enzymes within the cell phosphoiylatc vidarabine to the tn phosphate. which competes with deoxyadenosine phate for viral DNA polymerase. Vidarabine triphosphares also incorporated into cellular and viral DNA. where it a chain terminator. The triphosphatc form of vidarabinc also inhibits a set of enzymes that are involved in niethyla. tion of uridine to thymidine: ribonucleoside reductase. RNA polyadenylase. and S-adenosylhomocysteinc hydrolase. At one time in the United States, intravenous vidatabin was approved for use against HSV encephalitis. neonatal herpes, and herpes or varicella zoster in immunocompw mised patients. Acyclovir has supplanted vidarahine as is drug of choice in these cases. In the treatment of viral encephalitis. vidarabine had is be administered by constant flow intravenous infusion Is cause of its poor water solubility and rapid metabolic coma

sion to a hypoxanthine derivative in vivo. These coupled with the availability of less toxic and more agents, have caused intravenous vidarabine to be withdrasn

from the U. S. market.

HO'Thj

Vidarabinc occurs as a white, crystalline monohydrareths is soluble in water to the extent of 0.45 mg/mL at 25rC. drug is still available in the United States as a 3% Trlfluridine

for the treatment of HSV keratitis.

Chapter 1

• AntiriraI Agents

377

Acyclovir. USP. Acyclovir. 9-12-(hydroxyethoxy)methyIl.911-guanine (Zovirax). is the most effective of a series of acyclic nucleosides that possess antiviral activity. In contrast

teric properties (pK. values of 2.27 and 9.25). solubility is

with true nucleosides that have a ribose or a deoxyribose sugar attached to a purine or a pyrimidine base, the group attached to the base in acyclovir is similar to an open chain sugar, albeit Jacking in hydroxyl groups. The clinically use-

equivalent to 50 mg/mL of active acyclovir dissolved in sterile water for injection. Because the solution is strongly alkaII). it must be administered by slow, constant line (pH intravenous infusion to avoid irritation and thrombophlebitir, at the injection site. Adverse reactions are few. Some patients experience occasional gastrointestinal upset, dizziness, headache, lethargy. and joint pain. An ointment composed of 5% acyclovir in a polyethylene glycol base is available for the treatment of initial, mild episodes ol herpes genitalis. The ointment is not an effective preventer of recurrent episodes.

lul antiviral spectrum of acyclovir is limited to herpesviruses. It is most active (in vitro) against HSV type I. about 2 limes less against HSV type 2. and JO times less potent against varicella-zoster virus. An advantage is that uninfected human cells are unaffected by the drug.

0

increased by both strong acids and bases. The injectable form is the sodium salt, which is supplied usa lyophilized powder.

Valacyclovir Hydrochloride.

Valacyclovir (Valtrex) is the hydrochloride salt of the t.-valyl ester of acyclovir. The compound is a water-soluble crystalline solid, and it is a prodrug intended to increase the hioavailability of acyclovir by increasing lipophilicity. Valacyclovir is hydrolyzed rapidly and almost completely to acyclovir following oral ad-

OH N

0 Acyclovir

ministration. Enzymatic hydrolysis of the prodrug is believed to occur during enterohepatic cycling. The oral

bioavailability of valacyclovir is 3 to 5 times that of The ultimate effect of acyclovir is the inhibition of vir.rl

acyclovir. or about

DNA synthesis. Transport into the cell and monophosphory-

Valacyclovir ha.s been approved for the treatment of

lation are accomplished by a thymidinc kinase that is en-

herpes zoster (shingles) in immnunocompromised patients. The side effect profile observed with valacyclovir is comparable in bioequivalent doses of acyclovir. Less than 1% of

coded by the virus

The affinity of acyclovir for the

siral thyrnidine kinase is about 200 times that of the corresponding mammalian enzyme. Hence, some selectivity is attained. Enzymes in the infected cell catalyze the conversion of the monophosphate to acyclovir triphosphate. which

an administered dose of valacyclovir is recovered in the urine. Most of the dose is eliminated as acyclovir.

is present in 40 to 1(X) Limes greater concentrations in HSVinfected than uninfected cells. Acyclovir triphosphate competes for endogenous deoxyguanosine triphosphate (dGTP);

hence, acyclovir triphosphate competitively inhibits viral DNA polymerases. The triphosphorylated drug is also incor-

into viral DNA. where it acts as a chain terminator. Because it has no 3'- hydroxyl group. no 3'.5'-phosphodies. cr can fonts. This mechanism is essentially a suicide inhibition because the terminated DNA template containing

syclovir as a ligand binds to. and irreversibly inactivates, DNA polymeruse. Resistance to acyclovir can occur, most often by deficient thymidine kinase activity in HSV isolates. Acyckwir resistance in vesicular stomatitis virus (VSV) isoLas is caused by mutations in VSV thymidine kina.se or.

often. by mutations in viral DNA polymerase. Two dosage forms of acyclovir arc available for systemic ise: oral and parenteral. Oral acyclovir is used in the initial seatment of genital herpes and to control mild recurrent episodes. It has been approved fur short-term treatment of

Vatacyclovir

Ganciclovir. Ganciclovir. 9-1(1 .3-dihydroxy-2-propoxy)methyljguanine) or DHPG (Cytovene). is an analogue of acyclovir. with an additional hydroxymethyl group on the acyclic side chain.

and chickenpox caused by varicclla-zostcr virus VZV(. Intravenous administration is indicated for initial iM recunsent infections in immunocompromised patients for the prevention and treatment of severe episodes. The drug is absorbed slowly and incompletely from the gastroin-

tract, and its oral bioavailability is only 15 to 30%. Ncoertheless. acyclovir is distributed to virtually all body Less than 30% is bound to protein. Most of he drug is excreted unchanged in the urine, about 10% cxas the .carboxy metabolite. occurs as a chemically stable, white, crystalline that is slightly soluble in water. Because of its ampho-

Ganctctovir

378

Wilson and Gisvolds Texthook of Organic Medicinal

This structural modification, while maintaining the activity against HSV and VSV possessed by acyclovir. greatly enhances the activity against CMV infection. After administration, like acyclovir. ganciclovir is phosphorylaled inside the cell by a virally encoded protein kinose to the monophosphate,'7 Host ccli enzymes catalyze the formation of the triphosphate. which reaches more than I 0-fold

higher concentrations in infected cells than in uninfected cells. This selectivity is due to the entry and monophosphorylation step. Further phosphorylation with cellular enzymes occurs, and the triphosphate that is formed selectively inhib-

Pharn,aceuiical Chemisirs,

VS V-infected cells. penciclovir is first phosphorylated by viral thymidine kinasc4' and then further elaborated to the triphosphate by host cell kinases. Penciclovir triphosphate is a competitive inhibitor of viral DNA polymerase. The pharmacokinetic parameters of penciclovir are quite different from those of acyclovir. Although penciclovir triphos. phate is about 100-fold less potent in inhibiting viral DNA polymerase than acyclovir triphosphate. ii is present in the

its viral DNA polymerase. Ganciclovir triphosphate is also incorporated into viral DNA causing strand breakage and

tissues for longer periods and in much higher concentrations than acyclovir. Because it is possible to rotate the side chain of penciclovir into a pseudo-pentose. the metabolite possesses a 3'-hydroxyl group. This relationship is shown below with guanosine. Pcnciclovir is not an obli.

cessation of elongation.*u

gate chain terminator.4' hut it does co,npetitively inhibil

The clinical usefulness of ganciclovir is limited by the toxicity of the drug. Ganciclovir causes myelosupprcssion. producing neutropenia, thrombocytopenia. and anemia. These effects are probably associated with inhibition of host cell DNA Potential central nervous system

DNA elongation. Penciclovir is excreted mostly unchanged in the urine. 0

side effects include headaches, behavioral changes. and convulsions. Ganciclovir is mutagenic. carcinogenic, and teratogenie in animals.

Toxicity limits its therapeutic usefulness to the treatment and suppression of sight-threatening CMV retinitis in immunocomproinised patients and to the prevention of life-threatening CMV infections in at-risk transplant patients.2' Oral and ptuenteral dosage forms of ganciclovir are available, hut oral bioavailahility is poor. Only 5 to of an oral dose is absorbed. Intravenous administration is preferable. More than 90% of the unchanged drug is excreted in the urine. Ganciclovir for injection is available as a lyophilized sodium salt for reconstitution in normal saline. 5% dextrose in water, or lactated Ringer's solution. These solutions are

strongly alkaline (pH — II) and must be administered by slow, constant. intravenous infusion to avoid thrombophie-

H2N

N

HO

Guanosine

/

POnCICIOVIr

Penciclovir (Denvir) has been approved for the treatment of recurrent herpes labialis (cold sores) in adults It is effective against HSV-l and HSV-2.42 It is a cream containing 10% penciclovir.

bitis.

Famclclovir and Penciclovir.

Famciclovir is a diacetyl prodrug of pcnciclovir.4° As a prodrug. it lacks antiviral activity. Penciclovir. 9-14-hydroxy-3-hydroxymethylhut- 1-yll guanine. is an acyclic guanine nucleoside analogue. The structure is similar to that of acyclovir. except in penciclovir a side chain oxygen has been replaced by a carbon atom and an extra hydroxymethyl group is present. Inhibitory concen-

trations for HSV and VSV are typically within twice that of acyclovir. Penciclovir also inhibits the growth of hepatitis B virus.

Penciclovir inhibits viral DNA synthesis. In HSV- or

Cidofovir. Cidofovir. (S)-3-hydroxy-2-phosphononieui oxypropyl cylosine (HPMPC, Vistide). is an acyclonucles. tide analogue that possesses broad-spectrum activity agains several DNA viruses. Unlike other nucleotide analogues ilul are activated to nucleoside phosphates, Cidofovir is a plios phonic acid derivative. The phosphonic acid is not hydro lyzed by phosphatases in vivo but is phosphorylated by cells. lar kinases to yield a diphosphate. The diphosphate acts s. an antimctabolite to deoxycytosine triphosphate (dCTP), 0.

dotbvir diphosphate is a competitive inhibitor of viril DNA43 polymerase and can be incorporated into the growing

viral DNA strand, causing DNA chain termination.

0

Penctclovir

Chapter II • Anlñi rat Cidofovir posses.ses a high therapeutic index against CMV

379

palierns. Cidofovir is administered by slow, constant intrave-

bolic abnormalities including increases or decreases in blood Ca2 + levels. Ncphrotoxicity is common, and this side effect precludes the use of Fosearnet in other infections caused by

nous infusion in a dose of 5 tag/kg over a I-hour period once a week for 2 weeks. This treatment is followed by a maintenance dose every 2 weeks. AbOUt of a dose of

herpesvirus or us single-agent therapy HIV infection. Foscarnet is an excellent ligand for metal ion binding, which undoubtedly contributes to the electrolyte imbalances ob-

Cidofovir is excreted unchanged in the urine, with a of 2 to 3 hours. The diphosphate antiinetabolite. in contrast. has an extremely long half-life (17 to 30 hours).

The main dose-limiting toxicity of cidofovir involves

served with the use of the drug.TM' Hypocalcemia. hypomagneseinia. hypokalemia. and hypophosphatemia and hyperphusphatemia are observed in patients treated with foscarnet. Side effects such as paresthesias. tetani. seizures, and cardiac

renal impairment. Renal function must be monitored closely. with prohenecid and prehydration with intravenous normal saline can he used to reduce the nephrotoxieity of he drug. Patients must be advised that cidofovir is not a cure for CMV retinitis. The disease may progress during or

arrhythmias may result. Since foscarnet is nephrotoxic. it may augment the toxic effects of other nephrotoxic drugs. such as ainphotericin B and pentamidine. which are frequently used to control opportunistic infections in patients with AIDS.

been approved for treating CMV retinitis in AIDS

Foscamet sodium is available usa sterile solution intended

(stInts ing treatment.

for slow intravenous infusion. The solution is compatible with normal saline and

NH2

dextrose in water but is incompat-

ible with calcium-containing buffers such as lactated Ringer's solution and total parenterril ntltrition (TPN) preparatiruls. Foscarnet reacts chemically with acid salts such as tnidazolam. vancomycin. and pentamidine. Over 80% of an injected dose of fuscamet is excreted unchanged in the urine. ° The long elimination of foscarnet is thought to result from its reversible sequestration into

Reverse

OH

Cidofovir

Inhibitors

An early event in the replication of HIV-l is reverse transcription. whereby genomic RNA from the virus is converted

into a cDNA—RNA complex. then into double-stranded Trisodium phosphonofommtc is an inorganic pymphosphate analogue that inhibits replication in herpeoviruses (CMV. HSV. and VSV) and retroviruses IIIV).4* Foscarnet (Foscavir) is taken up slowly by the cells ad does not undergo significant intracellular metabolism. is a reversible. nonconipetitive inhibitor at the pyrophosphate-binding site of the viral l)NA polynterase and transcriptase. The ultimate is inhibition of the of pyrophusphate front deoxynucleotide triphosa cessation of the incorporation of nucleoside nphosphates into DNA (with the concomitant release of Since the inhibition is noncompetitive soh respect to nucleosidc triphosphate binding. foscarnet cnacl synergistically with nucleoside triphosphate arnime(e.g., zidovudine and didanosine triphosphates) in inhibition of viral DNA synthesis. Foscarnet does not Foscarnet Sodium.

rquirchioactivation by viral or cellular enzymes and. hetice. he effective against resistant viral strains that are deli— 'cii in virally encoded nucleuside kinases.°

DNA ready for integration into the host chromosome. The enzyme that catalyzes this set of reactions is reverse trimNeriptase. Reverse transcriptase actually operates twice prior to the integration step. Its first function is the creation of the cDNA—RNA complex; reverse transcriptase acts alone in this step. In the second step, the RNA chain is digested away by RNase H while reverse transcriptase creates the doublestranded unintcgratcd DNA. All of the classical antiretroviral agents are 2'.3'-dideoxynucleoside analogues. These compounds share a common

mechanism of action in inhibiting the reverse transcriptase of WV. Because reverse transcriptase acts early in the viral inlèction sequence, inhibitors of the enzyme block acute in-

fcction of cells httt are only weakly active in chronically inlècted ones. Even though the reverse transcriptase inhibitors share a common mechanism of action, their phamiaco-

logical atid toxicological profiles differ dramatically.

Zidovudine, USP. Zidovudine. 3'-azido-3'-deoxyihymidine or AZT. is an analogue of thymidine that possesses

antiviral activity against HIV-l. HIV-2. HTLV-l. and a

Na1!,

0 Na

Trisodlum Phosphonotormate

is a second-line drug for the treatment of retini— aimed by CMV in AIDS patients. The drug causes meta-

number of other retroviruses. This nucleoside was synthesized in 1978 by Lin and Prusofl°7 u.s an intermediate in the preparation of amino acid analogues of thymidine. A screening program directed toward the identification of agents potentially effective for the treatment of AIDS patients led to the discovery of its unique antiviral properties 7 years later.4M The next year. the clittical effectiveness of

AZ1' in patients with AIDS and AIDS-related complex (ARC) was demonstrated.49 AZT is active against retrovi-

380

Wll.an and Gisyold.r Textbook of Organic Medicinal and Pharmaceutical Chemi.cuy

ruses, a group of RNA viruses responsible for AIDS and some kinds of leukemia. Retroviruses possess a reverse Iran-

larly, where it inhibits reverse Iranscriptase and is incorpo-

scriptase or a RNA-directed DNA polymerase that directs the synthesis of a DNA copy (proviral DNA) of the viral RNA genome that is duplicated, circularized, and incorporated into the DNA of an infected cell. The drug enters the host cells by diffusion and is phosphorylated by cellular thymidine kinase. Thymidylate kinase then converts the monophosphate into diphosphates and triphosphates. The rate-determining step is conversion to the diphosphate, so high levels of monophosphorylated AZ'!' accumulate in the cell. Low levels of diphosphate and triphosphate axe present. Zidovudine triphosphate competitively inhibits reverse Iranscripiase with respect to thymidine triphosphate. The 3'azido group prevents formation of a 5',3'-phosphodiester bond, so AZT causes DNA chain termination, yielding an incomplete proviral DNA.5° Zidovudine monophosphate also competitively inhibits cellular thymidylate kinase. thus decreasing intracellular levels of thymidine triphosphate. The antiviral selectivity of AZ'!' is due to its greater (bOX)5' affinity for HIV reverse traxiscriptase than for human DNA polymerases. The human y-DNA polymerase of mitochondria is more sensitive to zidovudine; this may contribute to the toxicity associated with the drug's use. Resistance is common and is due to point mutations at multiple sites in reverse transcriptase, leading to a lower affinity for

infected cells. The potency of didanosine is 10- to 100-fold less than that of AZ'!' with respect to antiviral activity and cyrotoxicity. but the drug causes less myclosuppression than AZT causes.54 Didanosine is recommended for the treatment of patienis with advanced HIV infection who have received prolonged treatment with AZT but have become intolerant to. or experienced immunosuppression from, the drug. AZT and ddl act synergistically to inhibit H1V replication in vitro, and ddl effective against some AZT-resistant strains of HI V.53 Painful peripheral neuropathy (tingling, numbness, and pain in the hands and feet) and pancreatitis (nausea, abdominal pain. elevated amylase) are the major dose-limiting toxicities a) didanosine. Didanosine is given orally in the form ol buff-

rated into viral DNA to cause chain termination in HIV.

ered chewable tablets or as a solution prepared from the powder. Both oral dosage forms are buffered to present acidic decomposition of ddl to hypoxanthine in the stomach. Despite the buffering of the dosage forms, oral bioavailuhility is quite low and highly variable. Less than 20% of a dcc is excreted in the urine, which suggests extensive mc;aholism?6 Food interferes with absorption. so the oral drug niusi be given at least I hour before or 2 hours after meals. Highdose therapy can cause hyperuricensia in some patients

cause of the increased purine load.

the drug.52

Zidovudine is recommended for the management of adult patients with symptomatic HIV infection (AIDS or ARC) who have a history of confirmed Pneumocystis carinhl pneumonia or an absolute CD4 + (T4 or TH cell) lymphocyte count below 200/mm3 before therapy. The hematological toxicity of the drug precludes its use in asymptomatic patients. Anemia and granulocytopenia are the most common toxic effects associated with AZT. For oral administration, AZT is supplied as 100-mg capsules and as a syrup containing 10 mg AZ!' per mL. The injectable form of AZ!' contains 10 mg/mL and is injected intravenously. AZ'!' is absorbed rapidly from the gastrointestinal tract and distributes well into body compartments, including the cerebrospinal fluid (CSF). It is metabolized rapidly to an inactive glucuronide in the liver. Only about 15% is excreted unchanged. Because AZT is an aliphatic azide, it is heat and light sensitive. It should be protected from light and stored at 15 to 25°C.

0

Dldanostne

Zalcitabine.

Zalcitabine. 2'.3'-didcoxycytidine e USP. ddCyd. is an analogue of cylosine that demonstrates against HIV- I and HIV-2. including strains resistant to All The potency (in peripheral blood mononuclear cells) is s,mi tar to that of AZ'!'. but the drug is more active in of monocytes and macrophages as well as in resting cells Zalcitabine enters human cells by carrier-facilitated diffs sion and undergoes initial phosphorylation by deoxycytidinc kinase. The monophosphorylated compound is further nc tabolized to the active metabolite. dideoxycytidinc.5'-ti• phosphate (ddCTP). by cellular kinases57 ddCFP reverse transcriptase by competitive inhibition with dCTF.

Most likely, ddCTP causes termination of the viral DNA chain.

HoLd

Zalcitabine inhibits host mitochondrial DNA synthesis a low concentrations. This effect may contribute to its clinical toxicity.58

The oral bioavailability of zalcitabine is over Zidovudlne

Didanosine.

Didanosine (Videx, ddl) is 2',3'-dideoxyinosine (ddl), a synthetic purine nucleoside analogue that is bioactivated to 2',3'-dideoxy-ATP (ddATP) by host cellular enzymes.53 The melabolite, ddATP, accumulates iniracellu-

it

adults and less in children.5° The major dose-limiting Jilt effect is peripheral neuropathy. characterized by pain, pars thesias, and hypesthesia. beginning in the distal lower ci tremities. These side effects are typically evident alter wi eral months of therapy with zalcitabine. A potentially lati pancreatitis is another toxic effect of treatnnenl with ddf The drug has been approved for the treatment of HIV inlet

Chapter II U Anhiviral Ageiih.s

tarn in adults with advanced disease who arc intolerant to AZT or who have disease progression while receiving AZT. ddC is combined with AZT for the treatment of advanced HIV infection. NH2

381

It is interesting that the unnatural sterenisonler (—)-(S)ddC exhibits greater antiviral activity against HIV than the

natural enantiomer ( + )-(S)-ddC.65 Both enantiomers arc bioactivated by cellular kinases to the corresponding IriphosBoth SddCTP isomers inhibit HIV reverse transcriptase and are incorporated into viral DNA to cause chain termination. (+ )-S-ddCTP inhibits cellular DNA polymeruses much more strongly than (—)-SddCTP. explaining the greater toxicity associated with (+ )-(S)-ddC. Initial metabolic comparison of SddCTP isomers has failed to explain the greater potency of the (—I-isomer against HIV. Therefore, although the intracellular accumulation of ( — }-S-ddCTP

Zalcitabine

was twice that of (+ )-S-ddCTP. the latter was I / times more potent as an inhibitor of HIV reverse transcriptase. and the two isomers were incorporated into viral DNA at comparable rates. The puzzle was solved with the discovery

Stavudine.

Stavudine. 2'3'-didehydro-2'-deoxythymi-

dine (D4T, Zerit). is an unsaturated pyrimidine nucleoside that is related to thymidinc. The drug inhibits the replication o(HIV by a mechanism similar to that of its close congener. Stavudine is bioactivaced by cellular enzymes to a tiphosphate. The triphosphate competitively inhibits the incorporation of thymidine trtphosphate (TTP) into retroviral DNA by reverse transcriptase.°1 Stavudine also causes termi-

nation of viral DNA elongation through its incorporation no DNA.

0

of a cellular 3',S'-exonuclease. which was found to cleave terminal ( + )-S-ddCMP incorporated into viral DNA 6 times faster than (—)-S-ddCMP from the viral DNA terminus. Resistance to lamivudine develops rapidly as a result of a mutation in codon 184 of the gene that encodes Ff1 V-RT when the drug is used as monotherapy for I-f IV When combined with AZT. however. lamivudinc caused substantial increases in CD4' counts. The elevated counts were sustained over the course of therapy.67 The codon mutation that causes resistance to lamivudine suppresses AZT

resistance.67 thus increasing the susceptibility of the virus to the drug combination. NH2

Stavudine

Savudine is available as capsules for oral administration. The drug is acid stable and well absorbed (about 90%) following oral administration. Stavudine has a short Ito 2 hours) in plasma and is excreted largely unchanged '15 to 90%) in the urine.62 As with ddC. the primary doseeffect is peripheral neuropathy. At the recomdosages. approximately 15 to 20% of patients expesymptoms of peripheral neuropathy. Stavudine is recamended for the treatment of adults with advanced H1V who are intolerant of other approved therapies or havc experienced clinical or immunological deteriorawhile receiving these therapies. Lantlvudine.

OH

Lamivudine

Miscellaneous Nucleoside Antimetaboiftes Ribavirin, USP.

Ribavirin is l-$.o-ribofuranosyl-l,2.4-

thiazole-3-carboxamide. The compound is a purine nucleoside analogue with a modified base and a o-nbose sugar moiety. The structure of ribavirin is shown below.

Lamivudine is (—)-2'.3'-dideoxy-3'-thia-

(2R,5S)- 1.3-oxathiolanylcytosine. 3TC. or -i(.S)-ddC. Lamivudine is a synthetic nucleoside analogue differs from 2'.3'-dideoxycytidine (ddC) by the substitusn of a sulfur atom in place of a methylene group at the 3' of the ribose ring. In early clinical trials. lamivudine 4lidine.

highly promising antiretroviral activity against

PreimiIV and low toxicity in the dosages pharmacokinetic studies indicated that it exhibited good (F = —80%) and a plasma half-life of b 4 hours.°3

0H

Ribassrin

382

Wii.cg,n

and Gi.n'old'.c Textbook of Organic Medicinal and Phannaceujica! Chemistry

Ribavirin inhibits the replication of a very wide variety of RNA and DNA including orthomyxoviruses, paramyxoviruses,

been complicated by the fact that the vaccine apparently can

modulate its antigenic structures in its chronic infectious

arenaviruses, bunyaviruscs. herpesvi-

ruses. adenoviruses. poxvirus, vaccinia. influenza virus. parainfluenza virus, and rhinovirus. In spite of the broad spectrum of activity of ribavirin. the drug has been approved for only one therapeutic indication—the treatment of severe lower respiratory infections caused by RSV in carefully selected hospitalized infants and young children.

The mechanism of action of ribavirin is not known. The broad antiviral spectrum of ribavirin. however, suggests The nucleoside is bioactivated multiple modes of by viral and host cellular kinases to give the monophosphate

(RMP) and the triphosphate (RTP). RMP inhibits inosine monophosphate (IMP) dehydrogenase. thereby preventing the conversion of IMP to santhine monophosphate (XMP). XMP is required for guanosine triphosphate (GTP) synthesis. RTP inhibits viral RNA polymerascs. It also prevents the end capping of viral mRNA by inhibiting guanyl-N'methyltransferase. Emergence of viral resistance to ribavirin has not been documented. Ribavirin occurs as a white, crystalline, polymorphic solid that is soluble in water and chemically stable. It is supplied as a powder to be reconstituted in an aqueous aerosol con-

taining 20 mg/mL of sterile water. The aerosol is administered with a small-particle aerosol generator (SPAG). Deterioration in respiratory function, bacterial pneumonia, pncumothorax. and apnca have been reported in severely ill infants and children with RSV infection. The role of ribavirin in the-se events has not been determined. Anemia, headache. abdominal pain, and lethargy have been reported in patients

receiving oral ribavirin. Unlabeled uses of ribavirin include aerosol treatment of influenza types A and B and oral treatment of hepatitis, genital herpes, and La.ssa fever. Ribavirin does not protect cells

against the cytotoxic effects of the AIDS virus.

NEWER AGENTS FOR THE TREATMENT OF HIV INFECI ION When HIV- I was characterized and identified as the causa71 scientists from all over the tive agent of AIDS in world joined in the search for a prevention or cure for the

disease. Mapping the HIV-l genome and elucidating the replication cycle of the virus have supplied key information.72 Biochemical targets, many of which arc proteins involved in the replication cycle of the virus, have been cloned and sequenced. These have been used to develop rapid, mechanism-based assays\for the virus to complement tissue culture screens for whole-virus. Several of the biochemical steps that have been characterized have served as targets for clinical candidates as well as for successfully licensed

Vacdnes.

The chronology of vaccine development and use in the 20th century is nothing short of a medical miracle. Diseases such as smallpox and polio, which once ravaged large populations, have become distant memories. The tech. nique of sensitizing a human immune system by exposure to an antigen so that an anamnestic response is generated on subsequent exposure seems quite simple on the surface. Hence, it is natural that a vaccine approach to preventing AIDS be tried. The successes achieved so far have involved

live/attenuated or killed whole-cell vaccines and, in more recent times, recombinant coat proteins. Successes with vaccines of the live/attenuated (low-viw. lence), killed whole virus or the recombinant coal protein types have primarily involved acute viral diseases in which a natural infection and recovery lead to long-term immunity.

This type of immunity is of the humoral. or antibody. mediated, type, and it is the basis for successes in

ing the human population, Causative organisms of infections do not respond to vaccines. The AiDS virus causes a chronic disease in which infection persists despite a strong

antibody response to the virus (at least initially, HIV can circumvent the humoral response to infection by attacking and killing CD4 T cells). These T cells, also known as helper cells. upregulate the immune response. By eradicating

the CD4t cells, the HIV virus effectively destroys the irn mune system. Cell-mediated immune responses are critical

to the prevention and treatment of HIV infection. To be effective, a vaccine against HIV must elicit an appropriate cellular immune response in addition to a humoral response.

In other words, the vaccine must have the potential to xt on both branches of the immune system. The initial work on vaccine development focused on typic variants of the HIV envelope glycoprotein gpI2O cditamed by recombinant DNA techniques. This target was cbs. sen because of concerns about the safety of live/attenuated vaccines. The gpl 20 glycoprotemn is a coat protein, and if great care is taken, a virus-free vaccine is obtainable. Moreover. glycoprotein gp 120 is the primary target for neumihsing antibodies associated with the first (attachment) step rn HIV infection.77 Early vaccines were so ineffective that the

National Institutes of Health suspended plans for nlascivr clinical trials in high-risk individuals.75 There arc a numbs of reasons why the vaccine failed.7" There arc multiple subtypes of the virus throughout the the virus can by means of both cell-free and cell-associated forms; dir virus has demonstrated its own immunosuppressive. immunopathologicul, and infection-enhancing properties of parof the envelope glycoprotein; and vaccines have nor beer able to stimulate and maintain high enough levels of

drugs.73'

nity to be effective. The failure of the first generation of AIDS vaccines

Despite the many advances in the understanding of the HIV virus and its treatment, there is not yet a cure for the infection. Emergent resistance75 to clinically proven drugs

to a reexamination of the whole AIDS vaccine effort.75 As. guide for research efforts, a number of criteria for an "ide-il AIDS vaccine have been developed. The "ideal" AIDSue-

such as the reverse transcripta.se inhibitors and the protease

inhibitors has complicated the picture of good therapeutic

cine should (a) be safe, (Li) elicit a protective immure a sponse in a high proportion of vaccinated individuals, fri

targets. The idea of using a vaccine as a therapeutic tool has

stimulate both cellular and humoral branches of the immire

Chapter II

U Anti viral Agents

383

system, (d) protect components against all major HIV subtypes. (e) induce long-lasting protection. (I) induce local immunity in both genital and rectal mucosa, and (g) be practical tbr worldwide delivery and administration, It is not yet known how well the second-generation AIDS vaccines will satisfy the above criteria or when one might receive approval fur widespread use in humans. A new era in the treatment of AIDS and ARC was ushered in with the advent of some clinically useful, potent inhibitors of HIV. For the first time in the history of AIDS the death nile reversed itself. There arc several different classes of drugs that can be used to treat HIV infection. These are the nucleoside reverse transcriplase inhibitors (NRTIs). the nimnucleoside reverse transcriptase inhibitors (NNRTIs), the HIV protca.se inhibitors (Pis). the HIV entry inhibitors. and the I-IIV inlegrase inhibitors (IN). Presently. at least 14

coding for the enzyme. Cross-resistance between structurally

aniretruviral agenis belonging to three distinct classes NRTh. NNRTIs. PIs) have been licensed for use in patients

Nevirapine.

in the United States. All of these agents are limited by rapid

of resistance and cross-resistance, so commonly three drugs are used at the same time, each acting at a different point in HIV replication. These drugs can effect

dmniatic reductions in viral load, but eventually, as resisunce develops, the virus reasserts itself.

different NNRTIs is more common than between NNRTIs

and NRTIs. In the future, clinical use of the NNRTIs is expected to use combinations with the nucleosides to reduce toxicity to the latter. to take advantage of additive or syner-

gistic effects, and to reduce the emergence of viral resistance."'°° The tricyclic compound ncvirapine (Viramune).52 the bis(heteroacyl)piperazine (BHAP) derivative delaviradine (Rescriptor),83 and

have been approved

for use in combination with NRTIs such as AZF for the treatment of HIV infection. Numerous others, including the quinoxaline derivative the tetrahydroimidazobenzodiazpinone (TIBO) analogue R-829 and Calanolide-A'" are in clinical trials. Nevirapine (Viramunc)°2 is more than 90% absorbed by the oral route and is widely distributed throughout the body. It distributes well into breast milk and crosses the placenta. Transplacental concentrations are about 50% those of serum. The drug is extensively transformed by cyto-

chrome P450 to inactive hydroxylated metabolites; it may undergo enteruhepatic recycling. The half-life decreases from 45 to 23 hours over a 2- to 4-week period because of autoinduction. Elimination occurs through the kidney, with less than 3% of the parent compound excreted in the urine.82 Dosage forms are supplied as a 50 mg/S mL oral suspension and a 200-mg tablet.

Nonnucleoside Reverse Transcriptase InhIbitors (NIIIRTh) Cloned HIV- I reverse transcriptase facilitates the study of he effects of a novel compound on the kinetics of the en-

Random screening of chemical inventories by the p!unnaceutical industry has led to the discovery of several NNRTIs of the enzyme. These inhibitors represent several cauclurally distinct classes. The NNRTIs share a number of rominun biochemical and pharmacological properties.7't'50'8' Unlike the nucleoside antimelabolites. the NNRTIs do not rrqtire bioactivation by kinases to yield phosphate esters. The3' are not incorporated into the growing DNA chain. Inscal. they bind to an allosteric site that is distinct from the

(nucleoside triphosphate)-binding site of reverse tauscriptase. The inhibitor can combine with either free is substrate-bound enzyme. interfering with the action of both. Such binding distorts the enzyme so that it cannot ison the enzyme—substrate complex at its normal rate. :dl once formed, the complex does not decompose at the ssmal rate to yield products. Increasing the substrate ancentration

does

not reverse

these

effects.

Hence.

exhibit a classical noncompetitive inhibition pat:m with the enzyme.

The NNRTIs are extremely potent in in vitro cell culture

and inhibit HIV4 at nanomolar concentrations. I

inhibit reverse transcriptase selectively; they do not ihbit the reverse transcriptases of other retroviruses, in-

HIV-2 and simian immunodeficiency virus (Sly). NNRTIs have high therapeutic indices (in contrast to and do not inhibit mammalian DNA polyraiscs. The NRTIs and NNRTIs are expected to exhibit a srergisdc effect on HIV. since they interact with different

on the enzyme. The chief problem with the is the rapid emergence of resistance among HIV Resistance is due to point mutations in the gene

Newraplne

Delavirdine.

Delavirdine (Rescriptor)53 must be used with at least two additional antiretroviral agents to treat HIVI infections. The oral absorption of delavirdine is rapid, and peak plasma concentrations develop in I hour. Extensive metabolism occurs in the liver by cytochrome P-45() (CYP) isozyme 3A (CYP 3A) or possibly CYP 21)6. Bioavailability

is 85%. Unlike nevirapine. which is 48% protein bound, delavirdine is more than 98% protein bound. The half-life is 2 to II hours, and elimination is 44% in feces. 51% in urine, and less than 5% unchanged in urine. Delavirdine induces its own metabolism.81 Oral dosage forms are supplied as a 200-mg capsule and a 100-mg tablet.

Efavirenz. Efavirenz (Sustiva)84 is also mandated for use with at least two other antiretmviral agents. The compound is more than 99% protein bound, and CSF concentrations exceed the free fraction in the serum. Metabolism oc-

curs in the liver. The half-life of a single dose of cfavirenz is 52 to 76 hours. and 40 to 55 after multiple doses (the drug induces its own metabolism). Peak concentration is achieved

384

Wilwn, and Gisi'old's

of Organic Medicinal and Phannacewiral

Delavirdlne

in 3 to 8 hours. Elimination is 14 to 34% in urinc (as metabofiles) and 16 to 41% in feces (primarily as efavircnz).M The oral dosage form is supplied as a capsule. H

spread of cellular infection, they should possess good oral

bioavailability and a relatively long duration of action. A long half-life is also desirable because of the known develop.

rnent of resistance by HIV under selective antiviral Resistance develops by point mutations. Most of the early protease inhibitors are high-molecular.

sure.74

weight, dipeptide. or tripeptide-like structures. generall) with low water solubility. The bioavailability of these cons. pounds is low, and the half-life of elimination is very shon because of hydrolysis or hepatic metabolism.85 Strategic' aimed at increasing water solubility and metabolic

have led to the development of several highly promisini clinical candidates. Saquinavir indinavir(Crixi van).89 ritonavir (Norvir)."° nelfinavir (Viracept).9' and anprenavir (Agenerase)92 have been approved for the treatmcnl

HIV Protease Inhibitors

of HIV-infected patients. A number of others are in clinical trials.

A unique biochemical target in the HIV- I replication cycle

itors. As a class, they cause dyslipidernia, which includo

was revealed when HIV protease was cloned and cxin Escherichia coil. HIV protca.sc is an enzyme that cleaves gag-pro propeptides to yield active enzymes that

function in the maturation and propagation of new virus. The catalytically active protcase is a symmetric dimer of two identical 99 amino acid subunits, each contributing the triad Asp-Thr-Gly to the active The homodimer is unlike monomeric aspartyl prolea.ses (renin. pepsin. cathepsin D). which also have different substrate specilicities. The designs of sonic inhibitorsus '° for HIV- I protease exploit the C2 symmetry of the enzyme. HIV- I protease has active

site specificity for the triad Tyr-Phe-Pro in the unit Ser(Thr)-Xaa-Xaa-Tyr-Phe-Pro, where Xaa is an arbitrary amino acid. HIV prolease inhibitors arc designed to mimic the transition state of hydrolysis at the active site; these compounds are called analogue inhibitors. Hydrolysis of a pcptide bond

There is an important caution for the use of prolease inhib-

elevated cholesterol and triglycerides and a redistribution of body fat centrally to cause the . 'prolease paunch." buffalo hump, facial atrophy, and breast enlargement. These also cause hyperglycemia.

Saquinavir.

Saquinavir (!nvirase)'°' is wcll following oral administration. Absorption of saquinavis poor but is increased with a fatty meal. The drug does as distribute into the CSF. and it is approximately 98% bourd to plasma proteins. Saquinavir is extensively metabolizcd by the first-pass effect. Bioavailability is 4% from a hanl capsule and 12 to 15% from a soft capsule. Saquinavir p24 antigen levels in HIV-infected palienLs. elevates CD4 counts, and exerts a synergistic antiviral effect when corn bined with reverse transcriptase inhibitors such as AZI'anJ ddC.93-95 Although H!V- I resistance to saquinavir and

proceeds through a transition state that is sp3 hybridized and, hence, tetrahedral. The analogue inhibitors possess a preexisting sp7 hybridized center that will be drawn into the

HIV protease inhibitors occurs in vivo. it is believed to lv

active site (one hopes with high affinity) but will not be

tween different HIV protease inhibitors appears to be cono mon and additive.97 suggesting that using combinations sl inhibitors from this class would not constitute rational scribing. The drug should be used in combination with least two other antiretroviral drugs to minimize resistana Dosage forms arc Invirase (hard capsule) arid capsule).

cleavable by the enzyme. This principle has been used to prepare hundreds of potentially useful transition state inhibi-

Unfortunately, very few of these are likely to be clinically successful candidates for the treatment of HIV infection. Since HIV protease inhibitors arc aimed at arresting replication of the virus at the maturation step to prevent the

less stringent and less frequent than resistance to the reversc transcriptase inhibitorsY° Nevertheless, cross-resistance lv-

Chapter 11 • Anrivira! Age,,ts

385

H/

CH3

H3C

NH2

Saqulnavir

Sndinavir.

When administered with a high fat diet, mdi-

navir (Crixivan )50 achieves a maximum serum concentration A 77sf

ol the administered dose. The drug is 60% bound in the plasma. It is extensively metabolized by CYP 3A4, and seven nietabolites have been identified. Oral bioavailability is good. with a t,,, of 0.8 ± 0.3 hour. The half-life of elimination is 1.8 hour, and the elimination products are detectable in feces and urine. Indinavir also causes dyslipide-

ruts. The available dosage forms are capsules of 200, 333, and 4(X) mg.

high fraction of hepatic metabolism. Subsequent synthesis of

nonsXmmetric derivatives DMP-850'°' (below) and DMP-

851'' yielded in vitro antiviral potency comparable with that of the already-approved Pis. These were selected as clinical candidates on the basis of their favorable pharmacokinetics in dogs. In a second approach. random screening of chemical inventories yielded the 5,6-dehydropyran-2-one—

based inhibitor'02 PD-l78390 (below). This compound, in addition to having good potency against I-IIV protease and good anti-MW activity in cell culture, exhibits high bioavailability in experimental animals. PD- 178390 appears not to share the resistance profile of the other Pis, and no virus resistant to the compound emerged, even during the prolonged in vitro selection.

H

Indinavir

Ritonavir, Amprenavir, and Nelflnavlr.

Ritonavir

Nvrsir),°° ansprenavir IAgenerase),'tm and nelfinavir (Vira(see structures on page 386) have similar properties inJ cautionary statements. All cause dyslipidemia. and they use a host of drug interactions, mainly because they inhibit ('YP 3A4. These agents must always be used with at least soother antiretroviral agents. Used properly, the protease irhibitors are an important part of H!V therapy. A number ol nonpeptide inhibitors of HIV protease have ken developed as a result of two very different approaches. Fir enaniple,

DMP-850 CH3

CH

C2 symmetry of the active site of the en-

was exploited in the structure-based design of the symreinc cyclic urea derivative DMP-323.'°' This inhibitor cxpotent activity against the protease in vitro, excellent

activity in cell culture, and promising bioavailabilin experimental animals. In phase I clinical trials, howncr. the bioavailahility of DMP-323 was poor and highly ruhlc, possibly because of its low water solubility and a

OH

P0-178390

3

Dipeptide Pis containing 2-hydroxy-3-aminn-4-arylbutanoic acid in their scaffold showed promising preclinical results. JE-2 147103 (below), containing the allophenylnorostatin

386

of ()rgonie Medicinal

a,uI

Pljarnzacenzieal Che,,li%lrv

Rftonavir

Nelllnavfr

Amprenavir

JE-2147

Chapter II U

Ageittv

387

moiety, exhibited potent in vitro anti-WV activity. JE-2 147 a variety of HIV strains resistant to multiple approved Pls and exhibits good oral hioavailabilily and a good pharmacokinetic profile in two animal species. Also. emergence of resistance was considerably delayed with JE-2 147. R=

HIV Enhy Inhibitors Entry 01 HIV into a cell is a complex process that involves several specific membrane protein interactions. Initially. viral glycoprolein gpl2O mediates the virus attachment via its binding to at least two host membrane receptors. CD4 and die chemokinc coreceptor. This bivalent interaction induces a confomiational change in the viral fusion protein Protein gp4 I acts as the anchor for gp 120 in the virus. With the conformatinnal change, the viral envelope fuses sith the host cell membrane. In addition to gpI2O—chemokine receptor interaction, the fusion activity of gp4l is currently being explored as a novel target for antiretroviral

AMD-3100

Several positively charged 9-to 14-mer peplides have been described as capable of blocking the CXCR4 coreceptor. A small molecule. exhibits high-affinity binding to the CCR5 coreceptor, specifically blocking R5 isolates.

At least one agent from each class is in clinical tNing.

thetnakine

Receptor Binders

HIV-l isolates rely on the CCR5 corcceptor for entry strains). In later stages of the disease, however, more

Most

pathogenic selection variants of the virus emerge in about of individuals, which use the CXCR4 coreceptor in sidition to CCR5 (R5X4 strains) or the CXCR4 receptor only (X4 strains). Bicyclam compound AMD-3 lOOhbM was the first compound identified as a CXCR4-specific inhibitor dot interferes with the replication of X4 but not R5 viruses. The compound is currently in phase II clinical evaluations. It is used as an injectable agent because of its limited biosailahility.

TAK-779

Inhibitors of gp4l Fusion Activity The fusion of the HIV-l viral envelope with host plasnia

membrane is mediated by gp4 I. a transmcmhrane subunit of the H!V-l glycoprotein subunit complex. Pentafuside"5' (1-20) is a 36-mer peptide that is derived from the C-termi-

H

OR

Tetrazote

OH

II 0 R=benz

II

0 Diketo

388

Wilson and Gixt'old's Textbook of Organic Medicinal arid Pharn,act'nzical Clientistr

nal repeat of' gp4 I. Pentafuside appears to inhibit the forma-

lion of the fusion-competent conformation or gp4 I by inter-

feting with the interaction between its C- and N-terminal repeal. Penrafuside is a potent inhibitor of HIV-l clinical isolates, and it is currently in phase II clinical trials.

Integras. (IN) Inhibitors Two closely related types of small molecules that block strand transfer catalyzed by recombinant integrase have been

identified. Both types show in vitro antiviral activity. The diketo acids'°7 (above) inhibit strand transfer catalyzed by MutationS that conferred resistance to the diketo acids mapped near conserved residues in the IN enzyme. This finding demonstrates that the compounds have a highly specific mecharecombinant integra.se with an

less than 0.1

nism of action. X-ray crystallography of the hound teErazole°"t derivative (above) revealed that the inhibitor was centered in the active site of IN nearacidic catalytic residues.

Acknowledgment Portions of this text were taken from Dr. Arnold Martin's chapter in the tenth edition of this book. REFERENCES I. Condit, R. C.: Principles a?' sirnlogv. lit Knipe. D. M.. and P. St. teds.). l:untk,ntental Virology. 4th ed. New York. Lippincoit Williatius & Wilkins, 2(8)1. p. 19. 2. Hurnson. S. C.: Principles iii viral siruciure. tn Kitipe. t). M.. and Howlcy. P. M. (cdv.). Fundamecital Virology. 4th cii. New York. Lip. pincoit Williams & Wilkins. 2001. p. 53. 3. Wagner. F.. K., and Hewkn. M. J. teds.): Basic Virology. Maiden. MA. Blackweil Science. 999. p. t2. 4. Wagner. F.. K.. and Hewlett. M. .1. (cdv.): Basic Virology. MaIden. MA. Blackwell Science. t999. p.61. 5. Beak. J Jr.: Iminuncibiologicals. In Block. 3. H.. and Beak, J. M.. Jr teds.). Wilson and C,isvohd's Textbook or Organic Medicinal and Pharmaceutical Chemistry. 11th cii. Baltcntore, Lippincoit Williants & Wilkins, 2004. P. 10. 6. Freshicey. K. I.: Culture 01' Animal Cells. 3rd cii. New York, Witey. l,iss. 1994. 7. Young, .1. A. T.: Virus entry and uncoaticig. In Knipc. D, M.. and Hawley. P. M. teds.). Fundamental Virology. 4th ed. New York. Lippincoti Williams & 2001, P. 1(7. 8. tInnier. Ci: Virus assembly. In Knipc. D. Macid Hawley. P. M.(eds.). Fundamental Virology. 4th cvi. New York. l.ippincott Williams & Wilkins, 2001. p. 171. 9. Lamb. R. A.. and Clioppin. K. W.: Annu. Rev. Biochem. 52:467. 91)3.

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14. Haywootl. A. M.: J. Viral. 68:1. 1994. IS. Norkin. I.. C,: Clin. Microbial. Rev. 8:298—315, 1995. 16. ('hesehro, B.. Butler. R.. Portis. 3., ci ul.: 3. Viral. 64:215. 1990. 17. Clapham, P.R.. Blanc, I).. and Weiss. R. A.: Virology 181:703. 1991. IS. Harrington. K. 1).. and Gehalle. A. P.: 3. Viral. 67:5939. 1993. 19. Haywood, A. M.: 3 Viral. 6)1:1, 1994. 20. Young. 3. A. 1.: Virus entry and uncoating. In Knipc. I). M.. and Hawley. P. M. teds.). Fituidamenial Virology. 4th cd. New York. Lippicucoit Williams & Wilkins. 2001. p. 96

21. Wagner. F.. K.. and Hewlett. M. 3. teds.): Basic Virology Mahkn. MA, Itlackwell Science. 1999, p. 257 22. Mitsuya. H.. and BoxIer. S.: Proc. Nail. Aced. Sci. U.S.A. 83:1911. 1986.

23. Johnson, M. A.. vial.: 3. Bitt) Client. 263:1534. 1988. 24. Kohl, N. F... vi ul.: Proc Nail. Acad. Sci. Li. S. A. 85:4686. 988 25. Hay. A. J.: Sentin. Viral. 3:21. 1992. 26. Hayden, F. Ci.. llelsche. K. B.. Clover. R. I).. ci a?.: N. EngI. 1. Mrd 321:1696. l'J89. 27, Douglas, R. Ci: N. Engl. J. Mcd. 322:4-13. 1990. 28. Capparelli. E. V.. Stevens. R. C.. and Chow. M. S.' Cliii. Ther. 43:536. 1988. 29. Baron. S., ci ul.: Iniroductitiut to the interferon system. In t4amn, S. Diunzani. F.. Statiton. U. ci al. (cd.s.). Interferon: Priutciplcs and Mci))

cal Applicatiotis. Galveston, University of Texa.s. Texas McdirJ Branch, 1992, PP. I—IS. 30. Sen. Ci. C., md Ranco?uolf. R. M.: Ads. Virus Res. 32:57, 1993. 31. Bocci. V : HIV proteu.scs. In Baron, S.. Dian,.ant. F.. Stanton. 0.. Cl al. teds.). Interfcrc,n: Principles anti Medical Applications. Gulvestom University of Texas. 'l'cnas Medical Branch, 992. Pp. 417—125 32. Prusoff. W. H.: Idoxundine or how it all hegan. In DcClerq. F..

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5—24.

33. Birch, et iii.: 3. Infect Dis. 166:108, 1992. 34. Pnviim-Langsion, I).. ci a?.: Adenovine Arahinovude: An Auitishal Agent. New York, Raven 1975. 35. Schaeffer. H. 3.. ci at.: Naltire 272:583, 1978. 36. Weller. S.. ci al.: Cliii. I'harmactul. '18cr. 54:595, 1993. 37. Sullivan, V.. et al.: Nature 358:162. 1992. 38. Clair. M ci al.: Antimicrob. Agents Chemolher. 25:191. 1984 39. Faulds. I).. and Heel. K. C.: Drugs .19:597. 1990. 40. Vcrc Hedge. R. A.: Anuiviral Chem. Cheniotimer. 4:67. 1993. 41. Enrnshaw. I). L.. vi al.: Antinuicrub. Agents ('hcmotlier. 35:27i'. 1992.

42. Alr.mbia)i. F'. A.. and Saclis. S. L.: Drugs 52:17. 1996. 43. Xiung, X.. et al.: Biochem. Phannacol. 51:1562. 1996. 44. Chrisp. P.. and Chesso)d. S. I'.: Drugs 41:104. 199). 45. Cnmmpacker. C. S.: Am. J. Med. 92lSuppl. 2A:25, 1992. 46. Jacobson. SI. A., eta).: J. Clun. Endocrinol. Melab. 72:1130. 199) 47. Lin. 'I'. S., ant? Prusoff. %V. H.: 3. Med. Chcm. 21:109, 1978.

48. Miisuya. H., ci al.: Proc. Nail. Acad. Sd. 1). S. A. 82:7096. 985 49. Yarchoan. K., vi ii?.: l.anccl 1:575. 1986. 50. Furman. P. A.. ci al.: Proc. Nail. Acad. Sci. U.S. A. 873:8333. 51. St. Clair. M. Il..et al.: Antittiicrab. AgentsChemother.3 1:1972. Isil 52. Richman. I). I).. ci al.: J. Infect. t)is. 164:1075, 1991. 53. Johnson. M. A.. and Frimliand, A.: Mol. Ptuarunaicuil. 36:291, 989 54. McLarcn. C., eta?.: Aniivural Chenu. Chcmothcr. 2:32?. 1991.

55, Joluitson. V. A., ci al.: 3. Infect. 1)iv. 164:646. 99?. 56. Knupp. C. A.. ci al.: Clin. Pharmacol. Ther. 49:523. 1991. 57. Ynrchoan. K.. ci at.: N. EngI. 3. Med. 321:726. 989. 58. Chen, C.. M.. nit) Cheng. Y.: Mo). Pltamsacal, 625. 1991

59. Broder. S.: Am. 3. Mcd. t(8)Suppl. 5111:25. 1990. 60. Ho. H. 1., and Hitchcock. M. 3. M.: Antimicruib. Agents Chcmu'ilet 33:844. 1989. 61. Huang. P.. Farspihar, I).. and Plunkelt. W,: 3. Rio?. Client. 267:25C 992.

62. Brownc. M. 3.. ci a).: 3. InFect. Dis. 167:21. 1993. 63. Van l.ceuwen. K.. ci at.: J. Inteci. Di'.. 171:1166. 1995. 64. Pluda. 3. M.. ci al.: 1. InFect. Div. 171:1438, 1995. 65. Crates. 3. A. V.. ci al.: Antimicruth. Agents ('hcmother..96:202. )9) 66. Skulski, V.. ci al.: 3. Biol. Clicm. 268:23234. 1993. 67. Larder. B. A., ci al.: Science 21u9:6')6. 995. 68. Sudwell, R. W., ci al.: Science 77:705, 1972. 69. Robins. R. K : ('hon. Lug. News Jan. 27:28. 1986, 70. Gallo. R. C., ci al.: Science 220:865, 1983. 71. F.. ci il.: Science 2211:86)1, 1983. 72. Ha.scli.nc. W. A.: FASEB 3. 5:2349, 1991. 73. Yarchoan. R.. Milsuya. H.. and Broder. S.: Trends l'harniact,l 14::196. 1993.

74. DcClerq. B.: J. Med. Chem.38:2491. 1995. 75. Riclminan. I). D.: Aitnu. Rev. Pliarmuco). Toxicol .32:149, 1993 76. Cease. K. B.. and Ber,.uufvky, J. A.: Atiiiu. Rev. Iminunol. 2.92' 1994.

77. Lasky. L. A.. ci al.: Science 23:2119.

91)6.

Chapter 11 • Antit'iral Agents Cohen, J.: Science 264:1839. 1994. Roll. W. C.: Science 266:1335. 1994. Spcncc. R. A.. ci al.: Science 267:988. 1995.

Vacca. J. P., ci al.: Proc. Nail. Acad. Sd. U. S. A. '11:4096. 1994. Merle,.,,. U. T.. ci a!.: Science 250:1411. 1990. Ron,cr,. I). L: Drugs Future 19:7. 1994. Pedersen, 0.. and Pedersen, E.: Antivir,tl Chem. Chemother. 10:2115.

I'm. Pialoux. (3.. ci al.: Lancet 338:140. 1991, Wl,xlasser. R.. and Erickson. I. W.: Annu. Rev. Biochem. 62:543. 1993.

Chow. Y.-X.. ci al.: Nature 361:650. 1993. Roberts, N. A.. ci ul.: Science 248:358. 1990. Kun. U. E. ci at.: J. Am. Chem. Soc. 117:11111, 1995. Kenipl, D. J.. ci nI.: Proc. Nail, Acad. Sci. U. S. A. 92:2484. 995. Nclljnavjr. Si. Louis. Facts and Comparisons, 2000. p. 1431. Kageyania. S.. ci at.: Antitnicrub. Agents Chcmoilmer.37:8 III, 1993.

389

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94. Johnson, V. A.. Mcn'iIl. D. P., Chon, T.-C.. and Hirsch. M. S.: 3. Infect. Dis. 166:1143. 1992. 95. Craig. J. C.. ci a!.: Antivir.iI Cheni. Chemoilicr. 4:161. 1993. 96. Craig, 3. C.. ci a!.: Antiviral Chem. Chcrnnthcr. 4:335. 1993. 97. Condra, 3. H.. et jI.: Nature 374:569, 1995. 98. Wei, X., ci al.: Naturc 373:117. 995. 99. Ho, I). I).. ci al.: Nature 373:123. 995. 00. Kageyama. S.. ci al.: Aniltimicomb. Agents Chernoliicr.37:810. 1993. (II. DcLucca, (Let al.: Pharm. Bioicchnol. 11:257. 1998. 02. Prusad. 3.. ci al.: Bioorg. Med. Chem. 7:2775. 999. 11)3. Yoshimura. K., ci al.: Proc. Nail. Acad. Sd. U.S.A.. 96:8675. 1999. 11)4. Hendrix. C.. ci al.: 6th Conference on Rctrovirusc'. and Opportunistic Itilectiuns. Absir. 610. 1999. 105. Baba, M., ci al.: Proc. Nail. Aced. Sd. U. S. A. 96:5698. 1999. 106. Wild, C.. ci al.: Proc. Nail. Acad. Sci. U.S. A. 91:9770, 1994. 107. Hmw.ttdmt, D., ci a!.: Science 287:(,46, 2000.

108. Goldgur. Y. ci al.: Proc. Nat!. Acad. Sd. U. S. A. 96:13041), 999.

CHAPTER 12 Antineoplastic Agents WILLIAM A. REMERS

The chemotherapy ol neoplastic disease has become increas-

ingly important in recent years. An indication of this importance is the establishment ola medical specialty in oncology. in which the physician practices various protocols of adjuvant therapy. Most cancer patients now receive some form of chemotherapy. even though it is merely palliative in many cases. The relatively high toxicity of most anticancer drugs has fostered the development of supplementary drugs that may alleviate these toxic effects or stimulate the regrowth of depleted normal cells. The terms cancer and neoplas lie disease actually encom-

pass more than 100 different tumors, each with its own unique characteristics. Drugs active against a cancer of one tissue often are ineffective against cancers of other tissues. Even cancers of the same apparent type respond widely to a particular therapeutic protocol. Consequently, it has been

titative. Another difference is that immune mechanisms and other host defenses are very important in killing bacteria and other foreign cells, whereas they play a lesser role in killing cancer cells. cancer cells overexpress certain

antigens, and antibodies produced by recombinant DNA technology exert a selective cytotoxic effect on them. Quan.

titative differences in proteins found in signaling that control ccli proliferation, differentiation, and the induction of programmed cell death (apoptosis) also provide targets for anticancer drugs.2 Because cancer cells have over-

come the body's surveillance system. chemotherapeutic agents must kill every clonogenic malignant cell, because even one can reestablish the tumor. This kind of kill is Cxtremely difficult to effect because antineoplastic agents kill

Cancer chemotherapy has received no spectacular breakthrough of the kind that the discovery of penicillin provided for antibacterial chemotherapy. There has been substantial progress in many aspects of cancer research, however. In particular. an increased understanding of tumor biology has led to elucidation of the mechanisms of action for antineoplastic agents. It also has provided a basis for the more ra-

cells by first-order kinetics. That is. they kill a constant frac [ion of cells. Suppose that a patient had a trillion leukemia cells. This amount would cause a serious debilitation. A tent anticancer drug might reduce this population 10.000fold, in which case the symptoms would be alleviated and the patient would be in a state of remission. After cessation of therapy, however, the remaining hundred million leukemia cells could readily increase to the original number. Fur. thermore. a higher proportion of resistant cells would be present, which would mean that retreatment with the same agent would achieve a lesser response than before. For this

tional design of new agents. Recent advances in clinical tech-

reason, multiple drug regimens are used to reduce drasticafi>

niques, including large cooperative studies, are allowing

the number of neoplastic cells. Typical protocols for letikemia contain four different anticancer drugs. usually with dii. ferent modes of action.

difficult to make progress on a broad front of neoplastic diseases.

more rapid and reliable evaluation of new drugs. The combi-

nation of these advantages with improved preliminary screening systems is enhancing the emergence of newer and more potent compounds. At present, at least 10 different neoplasms can be "cured" by chemotherapy in most patients. Cure is defined here as

an expectation of normal longevity. These neoplasms are acute leukemia in children. Burkitt's lymphoma. choriocarcinoma in women. Ewing's sarcoma, Hodgkin's disease. lymphosarcoma, mycosis fungoides. rhabdomyosarcoma. retinoblastonia in children, and testicular carcinoma.1 Unfor-

tunately, only these relatively rare neoplasms are readily curable. Considerable progress is being made in the treatment of breast cancer by combination drug therapy. For carcinoma of the pancreas. colon, liver, or lung (except small cell carcinoma), however, the outlook is bleak. Short-term remissions are the best that can be expected for most patients with these diseases. There arc cogent reasons why cancer is more difficult to cure than bacterial infections. One is that there are qualitative differences between human and bacterial cells. For example, bacterial cells have distinctive cell walls, and their ribosomes differ from those of human cells. In contrast, the differences between normal and neoplastic human cells are mostly quan-

390

TUMOR CELL PROPERTIES The basic differences between cancer cells and normal cclh are uncontrolled cell proliferation, decreased cellular differ entiation, ability to invade surrounding tissue, and ability r establish new growth at ectopic sites (metastasis). Cornea) to popular belief, not all tumor cells proliferate rapidly. Pro-

liferation rates vary widely with the cell type. Thus. lym phomas and normal intestinal mucosa both proliferate faster than solid tumors. Acute leukemia cells actually proliferale

more slowly than the corresponding precursors in normal hone marrow. Development and homeostasis in multicellular organisno are controlled by processes of cell division. differentiation and death. In the adult, the steady-state number of differentiated cells is maintained by a balance between cell lion and cell death. Cell death is a complex and actixci) regulated process known as apoprosis. Apoptosis isa process of cell shrinkage, membrane blebbing. and nuclear condensation. It differs from necrosis, the cell death induced

Chapter 12 • Anhineoplastir Agents by severe cellular injury, which is characterized by swelling

391

If

and ysis.

The process of apoplosis is a complex but carefully orchestrated sequence of events. Scientists disagree on the rela-

sivc importance of factors such as mitochondrial damage. although many think that when stress factors reach a critical level, the mitochondrial membrane potential changes, and the nrjtochondria leak or rupture, resulting in their own destntction. This causes the release of factors that trigger proteolytie enzymes called caspases. Other investigators think that the primary apoptotic signals activate caspases directly and then caspases attack mitochondria along with other eeldat organdIes. Cancer can be considered a failure of cells to undergo apopiosis. In normal cells, sensors to cell abnormalities lead to withdrawal of survival signals. resulting in cell death. In contrast, cancer cells circumvent the need for survival signals by increasing their abundance of anti-apoptotic proteins. Among these anti-apoptotic proteins, members of the Bcl-2

(I)

cell cycle specific

cell cycle nonspecific 1

Drug Concentration

family, including BAX and BAK. have been identified with the initiation or progression of a variety of tumors. They block the release of cylochrome C and apoptosis.activating

FIgure 12—2 • Cell cycle specificity.

factor from mitochondria. Cells also have a variety of tumor suppressor proteins that

or transcription of nucleic acids or prevent cell division by interfering with mitotic spindles. Cells in the DNA synthesis or mitosis phases are highly susceptible to these agents. In

respond to DNA damage by shutting down cell division or by inducing apoptosis. One intensively studied protein is p53. which binds to the regulatory sequence of genes and inhibits their transcription. Many mutations produce p53 in amisiolded ftrm, resulting in a conformation unsuitable for binding to regulatory sequences. The development of half all cancers is thought to result from misfolding of p53. Recent research has produced compounds that restore p53 ro its acIivd conformation. The concept of a cell cycle is based on experiments using

'Hithymidine radiography and flow cytometry. These ax'eriments showed that DNA synthesis. as measured by inLvrporation of I'Hlthymidine. takes place at a specific pe-

nal, known as the S phase. in the life cycle of a dividing celL Periods between the S phase and cell division (niltosis tM phase) are termed G1 and G2. A circular pictorial model Fig. 12.1) was derived for the clockwise progression of the cell cycle. The duration oleach phase in the cell cycle varies considerably with the cell type and within a single tumor. Typical durations are as follows: S. 10 to 20 hours, 62. 2 u U) hours, and M. 0.5 to I hour. G1 is highly variable as l'ercsuli of another phase, G15. in which the cell is not active seeR division. Most anticancer drugs block the biosynthesis

C M Mitosis

G2 Resting

G1 R

S DNA Replication

FIgure 12—1 • The cell life cycle.

contrast, cells in the resting state are resistant to many agents.

Slow-growing tumors characteristically have many cells in the resting state.3 Antitumor agents are classified on the basis of their effects

on cell survival as a function of dose. For many drugs, including alkylating agents, cell survival is exponentially related to dose, and a plot of log cell survival against drug concentration (Fig. 12-2) gives a straight line. These drugs exert their cytotoxicity regardless of the cell cycle phase and are termed non—cell cycle phase specific. Other drugs.

including antimetabolites and mitotic inhibitors, which act at one phase of the cell cycle (cell cycle phase specific). show a plateau after an initial low-dose exponential region. The proportion of labeled cells in tissue after a specified interval (usually I hour) following injection of l3Hlthymidine or 5-bromodeoxyuridine is known as the labeling index (LI). Comparisonof the LI with the proportion of proliferat-

ing cells in DNA synthesis provides the growth fraction. Doubling times for tumor growth are calculated from the growth fraction and cell cycle times. Rarely are they as rapid

as predicted because of tumor cell loss through necrosis. metastasis, and differentiation. The cell-kill hypothesis states that the effects of antitumor drugs on tumor cell populations follow first-order kinetics. This means that the number of cells killed is proportional to the dose. Thus, chemotherapy follows an exponential or log-kill model in which a constant proportion, not a constant number, of cancer cells are killed.4 Theoretically, the fractional reductions possible with cancer chemotherapy can never reduce tumor populations to zero. Complete eradication requires another effect, such as the immune response. A modified form of the first-order log-kill hypothesis holds that tumor regressions produced by chemotherapy are descnbed by the relative growth fraction present in the tumor at the time of treatment. This idea is consistent with the finding that very small and very large tumors are less responsive than tumors of intennediate size.5

392

lVjl.wn, ciiul Gi.sI'okl.%

of

Medicinal mid Phanmueuiical

Stern cells arc the cells of origin of a cell line, which

1949. 6-mercaptopurmne iii 1952, and 5-fluorouracil in 1957.

maintain the potential to regenerate the cell population and from which the differentiated cells are derived. They are important in the chemotherapy of human tumors because they must be eradicated completely to effect a cure. Treatments that afford substantial reductions in tumor burdens

Additional alkylating agents such as mclphalan and cyclophosphuinide were developed during this period, arid the activity of natural products such as actinomycin. mitoniycin C. and the sinca alkaloids was discovered. During the progress continued in all of these areas with the discovery of cytosine urahinuside. hleornycin. doxoruhicin, and car-

can produce remissions. hut the tumor may recur if some of the stem cells remain. Their eradication is difficult because many we in the GI) phase of the cell cycle.5 Drug resistance to chemotherapy usually involve.s the selection of certain cell populations. Populations of drug-resistant cells can he produced by clonal evolution or mutation. Drug-resistant cells in tissue culture are generated at a frequency consistent with known rates rif genetic mutation. Mutagenic agents increase the frequency of generation of drugresistant cells. This effect may have clinical importance because many antitumor agents are mutagenic. Intracellular effects that cause drug resistance may he secondary to cellu-

lar adaptation or altered enzyme lcvels or properties. For example, resistance to methotrexate involves increased lev-

els of the target enzyme. dihydrofolate reductasc! Other modes of resistance to antimctabolites include reduced drug transport into cells, reduced affinity of the molecular target, stimulation of alternate biosynthetic pathways. and impaired activation or increased metabolism of the drug. A major factor in resistance to alkylating agents is the ability of tumor cells to repair DNA lesions, such as cross-links and breakage of DNA strands caused by alkytation. Cells selected for re-

sistance to one drug may show cross-resistance to other drugs, even if their chemical structures are quite different: most of these drugs are derived from natural products, how-

ever. One type of molecular explanation for this tonu of multiple drug resistance is overexpression of niemubrane gly-

coproteins termed P-g!vcoproieins. which function as drug cfflux pumps. This overexpression is associate(I with gene amplification.2 Most antineoplastic drugs are highly toxic to the patient and must be administered with extrenme caution. Some of them require a clinical setting where supportive care is available. The toxicity usually involves rapidly proliferating tissues. such as bone marrow and the intestinal epithelium.

Individual drugs produce distinctive toxic effects on the heart. lungs. kidneys. and other organs, however. Chemotherapy is seldom the initial treatment used against cancer.

If the cancer is well defined and accessible, surgery is preferred. Skin cancers and certain localized tumors are treated by radiotherapy. Generally, chemotherapy is impor-

tant when the tumor is inoperable or has metastasized. Chemotherapy is finding increasing use as an "adjuvant" after surgery to ensure that few cells remain to regenerate the parent tumor. The era of chemotherapy of malignant disease was horn in 1941. when Huggins demonstrated that the administration of estrogens produced regressions of nietastatic prostate canIn the following year. Gilmnan arid others began clinical studies on the nitrogen mustards and discovered that mech-

lorethamine was effective against Hodgkin's disease and lymphosareoma' These same two diseases were treated with cortisone acetate in 1949, and dramatic, although temporary. remissions resulted. " The next decade was marked by the

design and discovery of antituetabolites: methotrexate in

rnustine. Novel structures such as procarbazi ne. ducarbazine.

and ds-platintimu complexes were liund to be highly active. In 1965. Kennedy reported that remissions occurred in of postmenopausal women with metastatic breast cancer on treatment svith high doses of estrogen. Much of the leadership and financial support for the devetopment of anlineoplastic drugs derives from the National Cancer Institute (NCI), In 1955. this organization established the Cancer Chemotherapy National Service Center (now the Division of Cancer Treatment) to coordinate a national untary cooperative cancer chemotherapy development prothis effort had evolved into a targeted drug gram. By development program. A massive screening system was established to discover new lead compounds. and tliousanth of samples have been submitted to it. The current highly automated NCI tumor cell culture screening system achieved operational status in 199(1. It emphasizes rigorous end points such as net cell killing and tumor regression, rather than earlier growth-inhibitory end points, and it uses a wide sail ely of specific types of cancer, including runny solid tumour models, in the initial stage of screening. New drug candidates are being screened at a rate of about 20.(XX) per year. with input divided about equally between pure compounds and extracts or fractions frotni natural products. The present in vitro screening panel contains 60 human tumor cell lines arranged in seven suhpanels that represent diverse histologes: leukemia, melanoma, lung, colon, kidney. ovary, awl brain. For routine evaluation, each sample is tested in a 2-day continuous drug exposure protocol using five log 4,-spaeed M for pure compounds and concentrations staning at 100 at

for extracts. Antitumor activities are conipured

three different levels of response.

is the

concentration that produces 5Qh% inhibition in cell prolifer-

ation relative to the control. TGI (tumor growth inhibitiniti is the drug concentration at which there is no net prolifeniis the lethal concentration of drug tha tion. and produces a 501% reduction in the ntmnmher of tun,or cell' relative to the control. The primary NCI screening data are reported in a mean graph format (Fig. 12-3 in which a vertical reference ban, obtained by averaging the negative log11, Gic,, values fur all of the cell lines tested, is plotted along the drug concentrutieri axis amid then horizontal ham-s are plotted for the individual negative log ,, of each line with respect to the vertical reference bar. This graphical representation provides a chan

acteristic fingerprint for a given compound, displaying the individual cell lines that are more sensitive than average (bars to the right of the reference) or less sensitive than average (bars to the left of the referemmce. Thus. Figure I!3 shows that colon cancer cell lines are miiore sensitive than

average to 5-lluorouracil (5-FU. whereas central system (CNS) cancer cell lines are more resistant than aser age to

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A secondary stage of preliminary screening on selected compounds is performed in vivo in xenograft models by using a subset of cell lines found to be active in the primary in vitro screen. Two xenograft models in current use are the severe combined immunodeficiency (SCUD) mouse and the

athymic nude mouse. Both of those mouse models have defi-

cient immune responses that permit transplantation of human tumor cells without rejection. Consequently, potential antitumor drugs may be tested against human tumors in an in vivo

model. These models predict human clinical tumor responses better than the older allograft models that were based

on transplanting mouse tumors such as P388 leukemia into the same strain 01 mouse (syngeneic tumors). The important antitumor drug paclitaxel was discovered by using a xenograft model. An in vitro system that is a good predictor of human clinical activity is the human-tumor-colony—forming assay (l-ITCFA). This system uses fresh human tumor tissue from it is valuable in selecting chemotheraindividual peutic agents for individual tumor types and occasionally specific patients. but its use in large-scale primary screening has not been feasible. Compounds with significant antitumor activity are subjected to prcclinical pharmacology and toxicology evaluation in mice and dogs. Clinical trials may be underwritten by the Nd. They involve three discrete phases. Phase I is the clinical pharmacology stage. The dosage schedule is developed, and toxicity parameters are established in it. Phase II involves the determination of activity against a 'signal" tumor panel, which includes both solid and hematological types. A broad-based multicenter study is usually undertaken in phase Ill. It features randomization schemes designed to statistically validate the efficacy of the new drug in comparison to alternative modalities of therapy. As might he anticipated, the design of clinical trials for antineoplastic agents is very complicated, especially in the matter of controls. Ethical considerations do not permit patients to be left untreated if any reasonable therapy is possible. A number of pharmaceutical industry laboratories and foreign institutions have made significant contributions to the development of anticancer drugs. Organizations such as the United Kingdom's Cancer Research Campaign, the European Organization for Research on the Treatment of Cancer,

and the Japanese Foundation for Cancer Research have broadened international cooperation in anticancer drug tosearch.

mechlorethamine) showed selective toxicity, especially to lymphoid tissue. This observation led to the crucial suggestion that nitrogen mustards be tested against tumors of the lymphoid system in animals. Success in this area was lot. lowed by cautious human trials that showed methchlore. thamine to be useful against Hodgkin's disease and certain lymphomas. This work was classified during World War Il but was finally published in a classical paper by Gilman and Phillips in 1946." This paper described the chemical transformation of nitrogen and sulfur mustards to cyclic "oniurn" cations and established the nucleus as the locus of their interaction with cancer cells. The now familiar pattern of toxicity to rapidly proliferating cells in hone marrow and the gastrointestinal tract was established. A!kvlasio,, is defined as the replacement of hydrogen on an atom by an alkyl group. The alkylation of nucleic acids or proteins involves a substitution reaction in which a flu. cleophilic atom (nu) of the biopolymer displaces a leaving group from the alkylating agent.

nu-H + alkyl-Y

alkyl-nu

+H

-1- Y

The reaction rate depends on the nucleophilicity of the atom (S. N. 0), which is greatly enhanced if the nucleophile is ionized. Hypothetically, the order of reactivity at physiological pH is ionized thiol. amine, ionized phosphate. and ionized carboxylic acid)6 Rate differences among various amines would depend on the degree to which they are proton. atcd and their conjugation with other groups. The N-i position of guanine in DNA (Scheme 12-5, below) is strongh nucleophilic. Reaction orders depend on the structure of the alkyluting agent. Methane sulfonates, epoxidcs, and aziridines give ond-order reactions that depend on concentrations of the a)kylating agent and nucleophile. The situation is more com(nitrogen mustards) and plex with haloalkylsulfides (sulfur mustards), because these molecuks undergo neighboring-group reactions in which the nitrogen

or sulfur atom displaces the halide to give strained. membered "onium" intennediates. These "oniuni" iota react with nucleophiles in second-order processes. The overall reaction kinetics depend on the relative rates of the two steps, however. In the case of mechlorethaminc. the aziridinium ion forms rapidly in water, but reaction with biological nucleophiles is slower. Thus, the kinetic' are second order.'7 in contrast, sulfur mustard forms the less stable episulfon

ALKYLATING AGENTS Toxic effects of sulfur mustard and ethyleneimine on ani-

mals were described in the 19th century)4 The powerful vesicant action of sulfur mustard led to its use in World War I, and medical examination of the victims revealed that tissues were damaged at sites distant from the area of conSuch systemic effects included leukopenia, bone marrow aplasia. lymphoid tissue suppression, and ulceration of

the gastrointestinal tract. Sulfur mustard was shown to be active against animal tumors, but it was too nonspecific for clinical use. A variety of nitrogen mustards were synthesized between the two world wars. Some of these compounds (e.g.,

ium ion more slowly than this ion reacts with biologic.il nucleophiles. Thus, the neighboring-group reaction is rate limiting, and the kinetics are lirst order.'5 Aryl-substituted nitrogen mustards such as chloran,budl are relatively stable to aziridinium ion formation because the aromatic ring decreases the nucleophilicity of the nitna gen atom. These mustards react according to first-order kinetics.'8 The stability of' chlorambucil allows it to be takesi

orally, whereas mechlorethamine is given by intravenou administration of freshly prepared solutions. The require ment for freshly prepared solutions is based on the gradunl decomposition of the aziridinium ion by interaction ssiti water.

_____

Chapter 12 • A,uineoplaszie Agt':,:s

CH2CH2CI verV

fast

CH

moderate

395

CH2CH2nu

N(CH2CH2CI)2 * H20

—. CH2CH2OH

Ethylene imines and epoxides arc strained ring systems, but they do not react u.s readily as aziridinium or episulfonurn ions with nucleophiles, Their reactions arc second order as! are enhanced by the presence of acid. °' Examples of antitumor agents containing ethyleneimine groups are triethylenemelaminc and thiotepa.

CH

—, HO—C—H H—C—OH

H

CH2Br Mitobomitol Triethytene Metamine

Thiotepa

Diaziquone is an investigational benzoquinonc substituted with ethyleneimine groups and carbamate groups, both of shich are cancerostatic)9 After activation by reduction of

be quinone ring to a hydroquinone. the ethyleneiminc

alkylate DNA to produce cross-links. DNA—protein cross-links also are formed. emups

Some

0

Dtanhydro.D-rnannitol

A somewhat different type of alkylating agent is the Nalkyl-N-nitrosourea. Compounds of this class are unstable in aqueous solution under physiological conditions. They produce carbonium ions (also called carbeniurn ions) that can alkylate and isocyanates that can carbamoylate. For example. methylnitrosourea decomposes initially to form isocyanic acid and methyldiazohydroxide. The latter species decomposes further to methyldiazonium ion and finally to methyl carbonium ion, the ultimate alkylating species.22

0

- NHCOC2H5

+ H20 —.

NI

C2H5OCNH

0

No

The use of epoxides as cross-linking agents in textile i?rnistry suggested that they be tried in cancer ehemotherSimple diepoxides such as I ,2:3,4-diepoxybutane

jawed clinical activity against Hodgkin's disease,2° but rue of these compounds became an established drug. Di(mitobronitol) gives the corresponding diep-

continuous titration at pH 8. This diepoxide (1,2: 5,6.dianhydroomannitol) shows potent alkylating activity esperimental tumors?' thus suggesting that dibroand related compounds such as dibromodulcitol et by way of the diepox ides.

Isocyanic Acid

I N2

Diaziquone

+ Diazohydroxide

+ 0H

Substituents on the nitrogen atoms of the nitrosourca influence the mechanism of decomposition in water, which determines the species generated and controls the biological effects. Carmustinc (BCNU) undergoes an abnormal basecatalyzed decomposition in which the urea oxygen displaces

chloride to give a cyclic intermediate (Scheme 12-I). This intermediate decomposes to vinyl diazo hydroxide. the precursor to vinyl carbonium ion, and 2-chioroethyl isocyanate. The latter species gives 2-chioroethylamine. an additional alkylating agent.22 Some clinically important alkylating agents are not active

until they have been transformed by metabolic processes. The leading example of this group is cyclophosphamide.

396

Wilxun and GLnold'.c Textbook of Organic Medicinal and Phannaceutical Chemistry

0 —H

II

CICH2C1-I2NCNHCH2CH2CI —' CICH2CH2N —C= NCH2CH2CI

0=N

O=N I

H2C=CHN=NOH + 0=CNCH2CH2CI H,O

I N2 + 0H

Scheme 12—1 • Decomposition

N

CO2 +

of carmustine (BCNU).

which is converted by hepatic cytochrome P.450 into the

1CH2CH2CI

corresponding 4-hydroxy derivative by way of the 4-hydroperoxy intermediate (Scheme 12-2). The 4-hydroxy derivajive is a carbinolamine in equilibrium with the open-chain amino aldehyde form. Nonenzymatic decomposition of the

latter form generates phosphoramide mustard and acrolein. Studies based on 31P nuclear magnetic resonance (NMR) have shown that the conjugate base of phosphoramide mustard cyclizes to an aziridinium ion,24 which is the principal cross-linking alkylator formed from cyclophosphamide. The maximal rate of cyclization occurs at pH 7.4. It was suggested that selective toxicity toward certain neoplastic cells

NHCH2CH2CI

Itostamide

Other examples of alkylating species are afforded by car-

binolamines as found in maytansine and vinylogous carbine-

lamines as found in certain pyrrolizine

might be based on their abnormally low pH. This would afford slower formation of aziridinium ions, which would

00

persist longer because of decreased inactivation by hydroxide ions.22

Cyclophosphamide has been resolved, and the enantiomers have been tested against tumors. The levorotatory form has twice the therapeutic index of the dextrorotatory form.24 Ifosfamide. an isomer of cyclophosphamide in which one of the 2-chloroethyl substitucnts is on the ring nitrogen, also

has potent antitumor activity. It requires activation by hepatic enzymes, but its metabolism is slower than that of and involves substantially more dechloroethylation, yielding a chioroacetate metabolite.

N'

0

CH2CH2CI

0

CH2CH2CI

H2N

0

0

II

0 Phosphoramide Mustard +

H2C=CHCHO Acrolam

Scheme 12—2 • Activation of cyclophosphamide.

Chapter 12 U Authwopiaxtic

0

397

example, the sesquiterpene helenalin has both of these systems.2°

OCNHCH3

CH3

/ 1NHCH3

H

0

0 CH2

Vinytogous Carbinolarnine

f4etenalin

Alkylation can also occur by free radical reactions. The

Pytrokzino Dioster

When mitomycin C is reduced enzyinatically to its semiquinone radical, disproportion and spontaneous elimination system. nf methanol afford the vinylogous Loss of the carbaninyloxy group from thIs system gives a stabilized carhoniuni ion that can alkylate DNA (Scheme 11'3). The first alkylation step results from opening of the uiridine ring, and together with the vinylogous carhinolam.

it allows mitomycin C to cross-link double-helical Molecules like mitomycin Care said to act by "bioeductive alkylation.''28 Another type of alkylating species occurs in a.$-unsatucarhonyl compounds. These compounds can alkylate nucleophiles by conjugate addition. Although there arc no

a chemical class prone to decomposilion in this manner. These compounds were tested as antitu-

inor agents in 1963. and one of them. procarbazine. was found to have a pronounced, but rather specific, effect on Hodgkin's disease.3° Procarbazinc is relatively stable at pH 7. but air oxidation to azoprocarbazine occurs readily in the

presence of metalloproteins. Isomerization of this azo compound to the corresponding hydrazone. followed by hy-

drolysis. gives methylhydr.tzine and p-formyl-N-isopropyl benzamide. The formation of methylhydrazine from procarbazine has been demonstrated in living Methylhydrazine is known to be oxidized to methyl diazine,

clinical agents of this type, many natural prod-

which can decompose to nitrogen, methyl radical, and hydrogen radical.32 The methyl group of ?rocarbazine is incorporated intact into cytoplasmic RNA: It has not been estab-

active against experimental tumors contain a-rnethylcne or a,fl-unsuturated ketone functionalitics. For

lished conclusively, however, that the methyl radical is the methylating species.

0

CH2OCONH2

CH2OCONH2

5 Dmsproporlionation

—CI-t3OH 11.1.

OH

CH2OCONH2

0

CH2OCONH2

DNA OH

NH3

N[jA kheme 12—3 • Mitomycin C activation and DNA alkylation.

398

Wilson and Gi.ci'o!ds

of Organic Medicinal and Pharmaceutical chesnis,rv

CH3N =

CONHCH(CH3)2

Aoprocarbaz,ne

Procarbazine

CH3. + H' + N2

CH3NNH

CH3NHNH2 +

Methyldiazine

Methyihydraz,ne

Dacarbazine was originally considered an antimetabolite because of its close resemblance to 5-aminoimidazolc-4-car-

helix, is slow and difficult. In contrast, if the two strands are cross-linked, they canitot separate. Hence, they renatuntle

boxamide. an intermediate in purine biosynthesis. II now

rapidly on cooling. Interstrand cross-linking occurs with

appears. however, to be an alkylating agent!4 The isolation of an N-demethyl metabolite suggested that there might be a sequence in which this metabolite was hydrolyzed to methyldiazohydroxide. a precursor to methylcarbonium ion.35 but it was found that this mecabolite was less activc than starting material against the Lewis lung tumor. An alternative mode

mechlorethamine and other "two-armed" mustards, but ac• cording to this test. husulfan appears to give intrastr-and

of action was proposed in which dacarbazine undergoes acid-catalyzed hydrolysis to a diazonium ion, which can react in this form or decompose to the corresponding carbonium ion (Scheme 12-4). Support for the latter mechanism was alforded by a correlation between the hydrolysis rates of phenyl-substituted dimethyltriazines and their antitumor activitics.3" The interaction of alkylating agents with macromolecules such as DNA and RNA has been studied extensively. No

mode of action for the lethality to cancer cells has been established conclusively, however. A good working model was developed for the alkylation of bacteria and viruses, hut there are uncertainties in extrapolating it to mammalian cells.

The present working hypothesis is that most alkylating agents produce cytotoxic. mutagenic. and carcinogenic effects by reacting with cellular DNA. They also react with RNA and proteins, but these effects are thought to be less significant!7 The most active clinical alkylating agents are

links.35

In DNA, the 7 position (nitrogen) ut guanine is especially susceptible to alkylation by mechlorethamine and other ni trogen mustards (Scheme 12-5)!" The alkylated structure has a positive charge in its imidazole ring, which renders the guanine—ribose linkage susceptible to cleavage. This cleavage results in the deletion of guanine. and the resulting "apurinic acid" ribose—phosphate link is readily hydrolyc

able. Alkylation of the imidazole ring also activates it to cleavage of the 8,9 bond.'6 Other consequences of the positively charged punne structure are facile exchange of the 8-hydrogen, which can be used as a probe for a shift to the enslized pyrimidine ring as the preferred tautonrer. The latter effect has been cited as a possible basis for abnormal base pairing in DNA replication, but this has not been ated. One example in which alkylation of guanine does lead to abnormal base pairing is the 0-6-ethylat ion produced ethyl methanesulfonate. This ethyl derivative pairs with thymine, whereas guanine normally pairs with cyto.sinc.4'

hifunctional compounds capable of cross-linking DNA. Agents such as methylnitrosourea that give simple alkylation are highly mutagenic relative to their cytotoxicity. The crosslinking process can be either intersirand or intrastrand. Interstrand links can be verified by a test based on the thermal denaturation and renaturation of DNA. When double-helical DNA is heated in water, it unwinds and the strands separate. Renaturation. in which the strands recombine in the double

NXCOI*12

CH

\CH3

H30

N2

N H

+

Dacarbazine

1.

CH

/ Scheme 12—4 • Activation of dacarbazine.

H

+ HON = NCH3 NH2

Chapter 12 • ,tn:üu'op!astir ,tgenls

399

H

-H

— P0-

0

CH3 OH

CH2CH2NCH2CH2CI

+

Scheme 12—5 • Alkylation of guanine in DNA. Other base positions of DNA attacked by alkylating agents jie N-2 and N-3 of guanine; N-3. N- I. and N-7 of adenine:

0.6 of thyminc; and N-3 of cytosine. The importance of these minor alkylation reactions is difficult to assess. The phosphate oxygens of DNA are alkylated to an appreciable extent, but the significance of this feature is unknown.42 Guanine is also implicated in the cross-linking of doubleDNA. Di(guanin-7-yl) derivatives have been identilied among the products of reaction with mechlorethamine.° Busulfan alkylation has given l'.4'-di(guanin-7-yl)-butanc.

this product is considered to have resulted from innastrand linking.35 Enzymatic hydrolysis of DNA crosslinked by mitomycin C has given fragments in which the mubiotic is covalently bound to the 2-amino groups of two liuaflOsine residues, presumably from opposite strands of the helix.40

Alkylating agents also interact with enzymes and other rrolcins. Thus, the repair enzyme DNA nucleotidyltransfer-

leukemia cells is inhibited strongly by BCNU. knuustine (CCNU). and 2-chioroethyl isocyanate. Because

was a poor inhibitor of this it was concluded that the main interaction with the azsmc was carbantoylation by the alkyl isocyanates gener. red in the decomposition of BCNU and Alkylating agents can damage tissues with low mitotic but they are most cytotoxic to rapidly proliferating oases that have large proportions of cells in cycle. Nucleic sida are especially susceptible to alkylation when their are changed or unpaired in the process of replicaalkylaling agents are most effective in the late li or S phases. Some alkylation may occur at any stage in cycle, but the resulting toxicity is usually expressed 4en cells enter the S phase (Fig. 12-I). Progression through the premitotic phase, and cell cycle is blocked at 'loxion fails.4a

If cells can repair damage to their DNA beflre the next cell division, the effects of alkylation will not be lethal. Cells have developed a complex mechanism to accomplish this repair. Initially, a recognition enzyme discovers an abnormal region in the DNA. This recognition brings about the operation of an endonucicase. which makes a single-strand break in the DNA. An exonuclease then renuwes a small segment of DNA containing the damaged buses. Finally, the DNA is restored to its original strtcture by replacing the bases and rejoining the strand.4' Thus, tumor cells with efficient repair mechanisms will be relatively resistant to alkylatiiig agents. Tumor cells outside the cell cycle, in the resting phase (Ge). will have a rather long time to repair their DNA. Thus, slow. growing tunu)rs should not respond well to alkylating agents. and this is observed clinically.

Products MechlorethMechiorethamine Hydrochloride, USP. amine hydrochloride. Mustargen. nitrogen mustard, HN.. NSC-762. 2.2-dichloro-N-methyldicthylamine hydrochloride, is prepared by treating 2.2'.unelhylimino)diethanol with thionyl chloride.47 It occurs as hygroscopic leaflets that are very soluble in water. The dry crystals are stable at tem-

peratures up to 40°C. They an.' very irritating to mucous harmful to eyes. The compound is supplied in rubber-stoppered vials containing a mixture of IC) tug of rnechlorethumine hydrochloride and 90 mg of sodium chloride. It is diluted with 10 mL of sterile water immediately before injection into a rapidly flowing intravenous infusion. Intracavity injections are sotnetimes given to control malignant etfusions.

The aziridiniuni ion tirmed from niechlorcthamine in body tluids is highly reactive. It acts on various cellular components within minutes of administration. Less than

401)

and

of

Medieinal and l'/,ar,,,aeeuiwa! Cht'n:isirv

0.01% is recovered unchanged in the urine. hut more than 50'% is excreted in urine as inactive metabolites in the first 24 hours.

Mechiorethamine is effective in l-lodgkin's disease. Current practice is to give it in combination with other agents. The combination with viucristinc (Oncovin). procarhaiine. and prednisonc, known as the MOPP regimen, was considered the treatment of choice. Other lyniphomas and mycosis fungoides can be treated with mechiorethamine. The most serious toxic reaction is hone marrow depression, which icsuits in leukopenia and thronibocytopenia. Emesis is prevalent and lasts about 8 hours. Nausea and anorexia persist longer. These gastrointestinal effects may be prevented by the antiemetic compound ondansetron. Inadvertent extravasation produces intense local reactions at the site of injection. If it occurs, the immediate application of sodium thiosulfate solution can protect the tissues thiosulfate ion reacts

very rapidly with the aiiridiitiuni ion formed from mechlor-

or under refrigeration br prolonged times. At tentper.ttures above 35°C. it liquifies and decomposition is more rapid. Ilosfamnidc usually is administered in a short infusion a 5% dextrose or normal saline. Use within 8 hours of reconsti-

tution is recommended. Pharmacokinctic studies indicate that it is handled in the same way as cyclophosphainide. except that metabolism is less extensive. There is an appareni

half-life of 7 hours and a urinary recovery of The Food and Drug Administration (FDA)—approved in dication for ifosfamide is in combination therapy for gent cell testicular Combination salvage regimens are effective against soft tissue sarcoma. ovarian and breast car-

cinonias. and leukemia. Us limiting toxicity is in the urinal) tract, especially hemorrhagic cystitis. which results fmm the excretion of ulkylating metabolites in the urinary

Vigorous hydration and/or administration of mesna arc needed to prevent bladder damage. Other toxieities inclu& nausea and vomiting. alopccia. and CNS effects.

ethaminc.

Melphalan. USP. Cyclophosphainide. CyCyclophosphamide. USP. loxan. NSC-2ô27 I. N.N-his(2-chloroethyl)Ielrahydro-2HI .3.2-oxazaphosphorine-2-amine-2-oxide. is prepared by treating his(2-chloroethyh-phosphoramide dichioride with propanolamine.45 The monohydrate is a low-melting solid that is very soluble in water. It is supplied as 25- and 50mg white tablets, as 50-mg-unit-dose cartons, and as a powder (1(X). 200. or 500 mg in sterile vials. For reconstitution. 5 mUlO() rug of Sterile Water for Injection. USP. is added. The oral dose of cyclophosphamide is 9(1% hiouvailahie. with an 8e4, first-pass loss. It must he metaboli,.ed by liver microsomes to become active. Among the melaholites. phos.

phoramide mustard has antitumor activity, and acrolein is toxic to the urinary bladder. The acrolein toxicity can be decreased by intravenous or oral administration of the sodiuin sah of 2.mercaptocthane sulfonic acid (mesnal. whose sulihydryl group gives conjugate addition to the double bond of acrolein.49 In the plasma, mesna forms a disulfide, which is converted selectively to the active sulthydryf in renal tubules.

Cyclophosphamide has advantages over other alkylating agents in that it is active orally and parenterally and can be given in fractionated doses over prolonged periods. It is active against multiple myeloma. chronic lymphocytic leukemia (CLL). and acute leukemia of children. In combination with oilier chemotherapeutic agents, it has given complete remissions and even cures in Burkeit's lymphoma and acute lymphohlastic leukemia (ALL) in The most frequently encountered toxic effects are alopecia. nausea, and vomiting. Leukopenia occurs, hut thrombocytopenia is less frequent than with other alkyluting agents. Sterile hemnorrhagic cystiis may result and even he fatal. Gonadal suppression has been reported in a number of patients.

Ifosfamide.

Ikisfamide, IFEX. Holoxan. NSC- 109724. 3-(2-chloroethyl)-21(2-chlortsrthyl)aminol-tetrahydro-2H. I.

3.2-oxazaphosphorine-2-oxide. isophospharmide. is prepared from 3-I (2—chloroethyl )aminolpropanol by treatment with

phosphorus oxychioride followed by It is supplied in I- and 3-g vials as an oil-white Iyophiliied powder. The intact vials may be stored at room temperature

Melphalan. Alkeran. mustard. NSC-8806. 4-bis(2-chloroethyl)amino-i.-phenylal. anine. is prepared by treating m..N-phthalimnido-p-aminophc.

nylalanine ethyl ester with ethylene oxide, followed by phorus oxychioride. and finally hydrolysis with hydrochknw acid.55 Scored 2-mg tablets are available for oral tion. Oral absorption is erratic and incomplete, with ahsolwc hioavailability ranging from 25 to 89%. A preparation kit provided for parcnterul formulation. It contains 100 mg ol mclphalau. which is dissolved in I niL of acid-alcohol solu

tion. and then combined with final diluent containing mg of dipotassium phosphate. 5.4 niL of propylene glyoit and Sterile Water for Injection. USP. to give 9 mL of sok tion. This preparation should be used promptly. There is no significant first-pass effect with melphalar but the drug is gr.rdually inactivated by nonensyniatic drolysis to nionohydroxy and dihydroxy Elirs inamion is hiphasic. with half-lives of 6 to 8 minutes 40 to 60 minutes. Most of the drug is cleared by nonrerui mechanisms.

Melphalan is active against multiple myeloma. It active against breast, testicular, and ovarian carcinoma.' The clinical toxicity is mainly hemanofogical. which mews that the blood count must be followed carefully. Nausea aid vomiting are infrequent, but alopecia occurs.

'NH3 Merphalan

Chlorambudil. USP.

Chloranxbucil. Leukeran. chlteaminophenc, NSC-3088. p-(di-2-chlorethyl)-aminoplrerylbutyric acid, is prepared by treating p-aminophenyihuiya

acid with ethylene oxide, followed by thionyl Chlorambucil is soluble in ether and aqueous alkali. Its absorption is efficient and reliable. Sugar-coated 2-mg aS lets are supplied. Chlor.unbucil acts most slowly and is the least toxic any nitrogen mustard derivative in use. It is indicated cially in treatment of CLL and primary macroglobuiincmu

I

Chapter 12 •

Attsüwoplas:ie Agt'n;s

401

Other indications are lymphosarcoma and Hodgkin's discaseY' Many patients develop progressive, but reversible. during treatment. Most patients also develop a dose-related and rapidly reversible ncutropcnia. For these

Carmustine. Carmustine. BiCNU. BCNU. NSC409962. I .3-bis(2-chloroethyl-l -nitrosourea. is synthesized

wacons. weekly blood counts are made to determine the total and differential leukocyte levels. The hemoglobin levels are

changes to an oily liquid at 27°C. This change is considered a sign of decomposition, and such samples should be discarded. Carmustine is most stable in petroleum ether or water at pH 4. It is administered intravenously because metabolism is very rapid. Some of the degradation products. however. have prolonged half-lives in plasma. Carmustine is supplied

also determined for monitoring both toxicity (low counts) and efficacy in CLL (raised counts). USP. Busulfan. Myleran. NSC-750. I .4-dimethnnesulfonyloxy)butane. is synthesized by treating 1.4butanediot with methanesulfonyl chloride in the presence of It is obtained as crystals that are soluble in acelone and alcohol. Although practically insoluble in water, it dissolves slowly on hydrolysis. It is. however, stable in dry (non. It is supplied as scored 2-mg tablets. Busulfan is welt absorbed orally and metabolized rapidly. Much of the drug undergoes a process known a.s sulfur

by treating l.3-bis(2-chlorocthyl)urea with sodium nitrite and formic a low-melting white powder that

stripping" in which interaction with thiol compounds such as glulathione or cysteine results in loss of two equivalents simethanesulfonic acid and formation of a cyclic sulfonium intermediate involving the sulfur atom of the thiol.6' Such intermediates arc stable in vitro, but in vivo. they

as 100-mg quantities of lyophilized powder. When it is diluted with 3 niL of the supplied sterile diluent. ethanol, and further diluted with 27 mL of sterile Water. a 10% ethanolic solution containing 3.3 mg/mI is obtained. Biotransformation of carmustine is rapid and extensive. with most of a dose recovered in urine as metubolites. The half-life has an a-phase half-life of 6.1 minutes and a /3phase half-life of 21.5 minutes.67 Because of its ability to cross the blood—brain barrier. carmustine is used against brain tumors and other tumors (e.g., leukemias) that have metastasized to the brain!" It also is used as secondary therapy in combination with other agents for Hodgkin's disease and other lymphomas. Multiple

ate readily converted into the metabolite 3-hydroxythiolaneIl-dioxide?'2 That the sulfur atom of this thiolane does not

myeloma responds to a combination of carmustine and prednisonc. Delayed myelosuppression is the most frequent and

come from a methanesulfonyl group was shown by the

serious toxicity. This condition usually develops 4 to 6

nearly quantitative isolation of labeled methanesulfonic acid in the urine when busulfan 35S is administered to

weeks after treatment. Thrombocytopenia is the most pronounced effect, followed by lettkopenia. Nausea and vomiting frequently occur about 2 hours after treatment. Carmustine is given as a single dose by intravenous injection at 1(X) to 200 mg/m2. A repeat course is not given until the blood elements retUrn to normal levels, which requires about 6 weeks.

Oral doses of husulfan are generally well tolerated. The ahoorption has zero-order kinetics, with a mean log time of 36 minutes and a 2-hour duration to the end of absorption.TM Values for mean plasma concentration X time are dose de-

with peak levels of 24 to 130 nglmL for 2- to 6mg doses. The half-life is 2.1 to 2.6 hours. The main therapeutic use of busulfan is in chronic granuheytic leukemia. Remissions are observed in 85 to 90% of patients after the first course of therapy; it is not curative. however. It is used in preparative regimens (bone marrow ablative) for bone marrow transplantation in patients with various leukemias. Toxic effects are mostly limited to myelauppression in which the depletion of thrombocytes may cad to hemorrhage. Blood counts should be done at least weekly, The rapid destruction of granulocytes can cause

which might result in kidney damage. This complication is prevented by using allopurinol. a xunthine aidase inhibitor.65

CH2—CH2

Lomustine.

Lomustine, CeeNU. CCNU. NSC-79037, I -(2-chlorethyl)I-3-cyclohexyl-l-nitrosourea. is synthesized by treating ethyl 5-(2-chloroethyl)-3-nitrosohydantoate with cyclohexylamine. followed by renitrosation of the resulting intermediate. I l-(2-chloroethyl)!-3-cyclohexyl-urea!'° It is sufficiently stable to metabolism to be administered orally. The high lipid solubility of lonnustine allows it to cross the

blood—brain barrier rapidly. Levels in the CSF are 50% higher than those in plasma. Lomustine is supplied in dose packs that contain two each of color-coded 100-. 40-. and 10-mg capsules. The total dose prescribed is obtained by appropriate combination of these capsules.

H

H

I

I

/SCH2?COR + 2CH3S03+

+HSCH2CCOR OSO2CH 3

NHR'

—.

NHR'

OH2

HO

\2O

HC — OH

/

0

402

Wilson and Gisi'old'.s Textbook of Organic Medicinal and Pharmaceutical Che,njsirv

Procarbazine has demonstrated activity against Hodgkins

disease. For this condition, it is used in combination with agents such as mechlorethamine, vincristine. and prednisonc

Lomusfine

Oral absorption of fomustine is nearly complete within 30 minutes. U is convened rapidly into cis- and trans-4-OH metabolites by liver microsomes. The half-life of the parent drug is 1.3 to 2.9 hours, and the peak concentration of metab-

olites is reached 2 to 4 hours after dosing. Lomustine is used against both primary and metastatic brain tumors and as secondary therapy in relapsed Hodgkin's disease. The most common adverse reactions are nausea and vomiting, thrombocytopenia. and leukopenia. As in the case of carmustine. the myelosuppression caused by lomustine is delayed.70 The recommended dosage of lomustine is 130 mg/rn2 orally every 6 weeks. A reduced dose is given to patients with

compromised bone marrow function,

Thiotepa, USP. Thiotepa. TSPA. NSC-6396, N,N',N"triethylene-thiophosphoramide. iris( I -aziridinyl)phosphinc

sulfide, is prepared by treating trichlorophosphine sulfide with aziridine7' and is obtained as a white powder that is water soluble. It is supplied in vials containing 15 mg of thiotepa. 80 mg of sodium chloride, and 50 mg of sodium bicarbonate. Sterile water is added to make an isotonic solu-

tion. Both the vials and solutions must be stored at 2 to 8°C, These solutions may be stored 5 days without loss of potency. Thiotepa blood levels decline in a rapid biphasic manner.

It is convened into TEPA by oxidative desulfurization, and TEPA levels exceed those of' thiotepa 2 hours after administration. Aziridine metabolism also occurs, with liberation of ethanolamine, Thiotepa has been tried against a wide variety of tumors and has given palliation in many types, although with varying frequencies. The most consistent results have been obtained in breast, ovarian, and bronchogenic carcinomas and

malignant lymphomas. It is a mainstay of high-dose regimens in treating solid tumors when followed by autologous

(MOPP program). Toxic effects, such as lcukopenia. bocytopenia. nausea, and vomiting, occur in most patienta. Neurological and dermatological effects also occur. Conciw rent intake of alcohol, certain amine drugs, and foods cow taming high tyramine levels is contraindicated. The weak monoamine oxidase-inhibiling properties of procarbaiinc may potentiate catechol amines to produce hypertension.

Dacarbazine. DTIC-Dome. DIC. DTIC Dacarbazine. NSC.45388. 5-(3,3-dimethyl-l-triazenyl)-IH-imidazok4 carboxamide, is prepared by treating the diazonium salt. piw

pared from 5.aminoimidazole-4-carboxamide, with ylamine in methanol.74 It is obtained as a colorless to colored solid that is very sensitive to light. It does not

but decomposes explosively when heated above Water solubility is good, but solutions must be from light. Dacarbazine is supplied in vials containing eithe 100 or 200 mg. When reconstituted with 9.9 and 19.7 niL respectively, of sterile water, these samples give solttion. containing 10 mglmL at pH 3.0 to 4.0. Such solutions nuy be stored at 4°C for 72 hours. injected dacarbazine disappears rapidly from plasma k cause of hepatic metabolism. The half-life is about 40 mit

utes. Excretion is by the renal tubules, and in the 6.how tic excretion fraction, 50% of the drug is intact and N-demethylated metabolite.75 Dacarbazine is indicated for the treatment of mctasiaut Combination with other antinec malignant melanoma.75' plastic drugs is superior to its use as a single agent. Anoreic nausea, and vomiting are the most frequent toxic reaction Leukopenia and thrombocytopenia. however. are the nw serious effects.75 Blood counts should be done, and 11th counts are too low, therapy should be temporarily Dacarbazine is also used in combination therapy for kin's disease. The recommended daily dosage is 2 to 4.5 mg/kg Ire

days. with repetition at 4-week intervals. Extravasation the drug during injection may result in severe pain.

bone marrow transplantation. It also is used to control intra-

cavity effusions resulting from neoplasms. Thiotepa

is

highly toxic to bone marrow, and blood counts arc necessary during therapy.

Procarbazine hyProcarbazine Hydrochloride, USP. drochloride, Matulane, MIH. NSC-77213, N-isopropyl-a(2-methylhydrazine)-p-toluamidc. is prepared from N-isopropyl.p-toluamide in a process involving condensation with

diethyl azodicarboxylate. methylation with methyl iodide and base, and acid hydrolysis.72 Although soluble in water, it is unstable in solution. Capsules containing the equivalent of 50 mg of procarbazine as its hydrochloride are supplied. Procarbazine is rapidly and completely absorbed following oral administration. It readily decomposes by chemical and metabolic routes, with a half-life of 7 to 10 minutes, to produce highly reactive species including methyl diazonium ion, methyl radicals, hydrogen peroxide. formaldehyde. and hydroxyl radicals.73

ANTIMETABOLITES Antimetabolites are compounds that prevent the biosynthe or use of normal cellular metabolites. Nearly all of the cit

cal agents are related to metabolites and cofactort, in biosynthesis of nucleic acids. They usually are lated in structure to the metabolite that is antagonized. ainimetabolites are enzyme inhibitors. They may comb with the active site as if they were the substrate or cofacin Alternatively, they may bind to an allosteric regulatory especially when they resemble the end product of a bios

thetic pathway under feedback control.11' antimetabolite must be transformed biosynthetically faa lized) into the active inhibitor. For example. tine is convened into the corresponding ribonuclcct which is a potent inhibitor of the conversion of bosylpyrophosphate into 5-phosphoribosylamine. a controlling step in the de novo synthesis of purinec5t

Chapter 12 U Antineoplast

H2O3P

H203P

HO

OH

OH

5-Phosptioribosylpyrophosptlate

Alp

5, lOMethenyl leirahydrolOlate

NH2

H2O3P

Formylgtycino

Ribonucleolide

G!utarnu,o

AlP.

H

NyM HN

JNH°

HO

OH

r

AlP

Mg.K N

HO2C

N

N

Ribonuclectide

N

H

I

H2O3P

H203P

HO

OH

Scheme 12—6 • De novo synthesis of purine nucleotides (simplified).

404

Wilson

and

of Organic Medicinal and Pharmaceutical Cliesnisirv

+ N

CH

0

LN

N

N

II

CH I

CO2H

HO

HO

HO

OH

Adenytosuccunic

IflOSifliC Acid

OH

Adenybc Acid (AMP)

Acid

0

N N

H203P

H203P

HO

OH

Guanylic Acid (GMP)

Xartthylic Acid

Scheme 12—6 • Continued.

Scheme 12-6). An auiiimctabolitc and its transformation product.s may inhibit a number of different enzymes. Thus, 6-mercaptopurine and its anabolitcs interact with more than 20 enzymes. This multiplicity of effects makes it difficult to decide which ones are crucial to the anticumor activity. The anabolites of purine and pyrimidine antagonists may be incorporated into nucleic acids. In this event, part of their

antitumor effect might result from malfunction of further macromolecular synthesis because of the abnormal nucleic acids.5'

After the formulation of the antimetabolite theory by Woods and Fildcs in 82O antimetabolites based on a variety of known nutrients were prepared. The first purine analogue to show antitumor activity in mice. 8-azaguanine. was This compound was introsynthesized by Roblin in

H3C—N.

0

S

duced into clinical trials hut was abandoned in favor ii newer and more effective agents, such as 6-mercaptopunv: and 6-Ihioguanine, developed by Hitchings and Mercaptopurine was synthesized in and was shre to be active against human leukemia in the lolkiwing To be active against neoplasms. 6-mercaptopurine mui be converted into its ribonucleotide, 6.ihioinosinate. by fr enzyme hypoxanthine-guanine Neoplasms that lack this enzyme are resistant to the 6-Thioinosinate is a potent inhibitor of the conversion phosphorihosylpyrophosphate into 5-phosphorihosybrnrni as mentioned above, It also inhibits the conversion of sinic acid to adenylic acid at two stages: (a) the reactkin ii inosinic acid with aspailate to give adenylosuccinic acid (h) the loss of fumaric acid from adcnylosuccinic acid I give adenylic acid.8' Furthermore. it inhibits the tixidali' of inosinic acid to xanthylic acid.85 The mode of artist ii 6-mercaptopurine is further complicated by the fact thz ribose diphosphate and (riphosphute anabolites are also tive enzyme inhibitors, and the triphosphate can be incotjt

rated into DNA and RNA to inhibit further chain ehsa

tion.°' Still more complex is the ability of H

to act as a substrate for a methyl tr.tnsfcrjse that tequila adenosylmethionine. which converts it into 6-niethylits'i

H

nosinate. The latter compound is responsible for certainali 8.Azaguanine

6-Mercaptopunne

Azathioprrie

metabolite activities of 6-mercaptopurine.8"

('hapter 12 • 6Thioinosinate

SR

Agenl.s

405

NH

= H) (R = CH.,)

LLT'N

P

Metabolic degradation (catabolism) of 6-mercaptopurine by guana.se gives 6-thioxanthine. which is oxidized by xanthine oxidase to yield 6-thiouric acid."° Allopurinol. an inhibitor of xanthinc oxidase. increases both the potency and toxicity of 6-mcrcaptopurinc. Its main importancc. howocr. is as an adjuvant to chemotherapy because it prevents uric acid kidney toxicity caused by the release of purines born destroyed cancer cells. Heterocyclic derivatives of 6-

such as azathioprine (Iniuran). were deto protect it from catabolic reactions.'° Although azahioprine has antitunlor activity, it is not significantly better than 6-mercuptopurine. It has an important role, however. an immunosuppressive agent in organ

P. = H Vidarabrie

A = F.

HOPO.. Fludaiabine

In contrast to the susceptibility of adenosine arahinoside to adenusinc deaminase. its 2-fluoro derivative, iludarabinc. is stable to this enzyme. Fludarahine is prepared as the 5'monophosphate. Fludarahine has good activity against CLL. Ii is converted into the corresponding triphosphate,'°1 which inhibits ribonucleotide reductasi' 2.Chloro.2'-deoxyadenosine (cladrihine) also is resistant to adenosine dcaniinusc. It is phosphorylated in cells to the triphosphate by cytidinc kinase. and the triphosphate inhibits enzymes required tbr DNA repair. Cladrihinc is highly effective against hairy cell leukemia. NH2 N

6-Thiouric Acid

Allopunnol

Thioguanine is converted into its rihonucteotide by the enzyme that acts on 6-mercaptopurine. It is converted These species inhibit the di- and nod of the same enzymes that are inhibited by 6-mercaptosiine. Thioguanine is also incorporated into RNA, and its

ntetabolite is incorporated into DNA. The signifithese "fraudulent" nucleic acids in lethality to neois uncertain.'3

Cladribine

The invention of 5.fluorouracil as an antimetaholile of uracil by Heidelberger in 1957 provided one of our toremost examples of rational drug design.'°1 Starting with the observation that in certain tumors uracil was used more than orotie acid, the major for nucleic acid pyrimidinc biosynthesis in normal hissue. he decided to synthesize an antimetaholite of uraeil with only one modification in the structure.

The 5 position was chosen fir a substituent to block the conversion of uridylate to thynsidylate (Scheme 12-7). thus diminishing DNA biosynthesis. Fluorine was chosen as the 6Thioguanine

substituent because the increased acidity caused by its induc-

tive effect was expected to cause the molecule to hind Adenine arabinoside (Vidarabine) was first prepared by bcmicat synthesis'TM and later isolated from cultures of a sugar. o-arahinosc. siqsornyces isepimeric with n-ribose at the 2' position. This strucchange makes it a competitive inhibitor of DNA polyIn addition to its anhineoplastic activity, adeninc .nbinosidc has potent antiviral action. Adeninc arabinoside

strongly to These choices were well tbunded. as 5-tluorourucil soon became one of the most widely used antineoplastic agents. H is a mainstay in the therapy of adenocarcinoma of the colon and rectum. Side arc both dose and schedule dependent. They include myelosuppression on bolos administration and mucositis on prolonged infusions. Otherwise, the drug is svcll tolerated.

of its derivatives are limited in their antitumor

5-Fluorouracil is activated by anabolism to 5-fluoro-2 dcoxyuridylic acid. This conversion may proceed by two

.d

to adenosinc deuminase. This enzyme

them into hypoxanthine arubinoside derivatives. resistance of certain tumors correlates with their levels aknminc dcaminasc."1

routes. In one route. 5-tluorouracil reacts with ribose- I phos. phale to give its riboside. which is phosphorylated by uridine kinase.'°2 The resulting compound. 5-Iluorouridylic acid, is

406

Wi/si,,, and Gisrold's ie'aI,oak of Organic Medicinal mid I'Izannaeeuzical Cl,enii.cirr

NH

Enzyme

Enzyme

2-Dooxyuridyiate

+

HN1

0 R=

CO,H R

Sdieme 12—7 • Conversion of uridylate

Thymidyiale

into thymidylate.

converted into its 2'-dcoxy derivative by ribonucleotide reductase. 5-Fluorouracil also may he iransforiiied directly into 5-tluorouridylic acid by a phosphoribosyltransferase. which is present in certain tumors. "° An alternative pharmaceutical

based on 5-fluorouracil is its 2-deoxyriboside (floxuridine).'0' This compound is phosphorylaled by 2'-dcoxyuridine kinase.

5-Fluoro-2'.deoxyuridylic acid is a powerful competitive inhibitor of thynlidylale synthetase. the enzyme that converts

2'-deoxyuridylic acid to thymidylic acid. This blockage is probably the main lethal effect of 5-fluorouracil and its melabolites. "° In the inhibiting reaction. the sultuiydryl group

IF

0

5-Fluorouracil

0

of a cysteine residue in the enzyme adds to the 6 of the fluorouracil moiety. The 5 position then hinds tei' methylene group of 5.1 O-mnethylcnetetrahydrololate. Oni

narily. this step would be followed by the transfer of thef hydrogen of uracil to the methylene group, resulting in formation of thymidylate and dihydrofolate: however. fluorine is stable to transfer, and a terminal product rad involving the enzyme. cofactor. and substrate, all bonded. Thus. 5-fl uoro-2'-deoxyuridylic acid would silied as a inhibitor."5 The rate-determining enzyme in 5-fluorouracil caiabo!hr is dihydropyrimidine dehydrogenase. Inhibition of thisn

0

0

HN)Lf F

HO

HO

OH

5-Fluorouiacil Riboside

5-Fluorodeoxyuuctylic Acid

5Fluorouracil 2-Deoxytiboside

Chapter 12 • Anhint'opia.crii Agents by 5-ethynyluracil increases the plasma concentrationcurve index IWO-

of 5-fluorouracil enough to raise its therapeutic to fourfold. NH2

NH2

407

In gemcitahinc. fluorine atoms replace the hydroxyt group and the hydrogen atom at the 2' position of After its anabolism to diphosphate and triphosphale metabolites. gemcilahine inhibits ribonucleotide reductase and competes

with 2'-deoxycytidine Iriphosphate for incorporation into DNA. These effects produce cell-cycle-specific cytotoxicity.

-

o

Gemcitabine has become a first-line treatment for locally advanced and nictastatic adenocarcinoina of the pancreas. Trifluorothymidine (Trifluridine) was designed by Heidel-

berger as an antimetaholite of thymine.'°' The rihoside is csseiilial because mammalian cells are unable to convert thymine and certain analogues into thymidinc and its analogues.

SHfl

Thymidine kinase converts trilluorothymidine into trifluorothymidylic acid, which is a potent inhibitor of thymidylate

synthetase." In contrast to the stability of most trilluoroR

Enzyme

The tetrahydrofuranyl derivative of 5-Iluorouracil. tegafur was prepared in Russia.101' It is active in clinical and less myclosuppressive than 5-fluorouracil. It has

castrointectinal and CNS toxicity, however. Tegafur is clowly metabolized to 5-fluorouracil: thus, it may he considfred a prodrug.'°7

methyl groups. that of Irifluorothynsidylic acid is extraordinarily labile. It reacts with glycinc to give an amide at neutral pH.' 0 Kinetic studies have shown that this reaction involves initial nucleophilic attack at position 6. followed by loss of HF to give the highly reactive difluoromethylenc group.°' Glycine then adds to this group and hydrolysis of the remaining two fluorine atoms follows (Scheme 12-to. The interac-

tion of trifluorothymidylic acid with thymidylate synthetase apparently follows a similar course. Thus, after preincubation. it becomes irreversibly hound to the enzyme. and the kinetics are tlonconnpetitive."°

IF 0

Cytosine arahinoside was synthesized in 1959h2 and later found as a fermentation Its structure is noteworthy in that the arabinose moiety is epimeric at the 2' position

with ribose. This modification, after anabolism to the iiiphosphate. causes it to inhibit the conversion of cytidylic acid to 2'-dcoxycytidylic acid.' '' For a number of years, this

inhibition was believed to be the main mode of action of cytosine arabinoside triphosphate: however, it was shown

Tegatur (Etorafur)

was designed rationally as a tumor-selective n,l tumor-activated prodrug of 5-fluorouracil, which would kss likely to produce severe diarrhea. It is a carbamate of 5'-deoxy.S-fluorocytidine. On oral administratie. ii is converted into 5'-deoxy-S-fluorocytidine by cytideaminase. which is in higher concentration in many urors than in most normal tissues, with the notable excep-

st liver. Activation to cytotoxic species by thymidinc occurs preferentially at tumor sites.10° Dcthis complex activation process. capecitabine still cxNbns sonic of the significant toxjcjties of 5-Iluorouracil. NHCOC5H11

recently that various deoxyrihonucleosides were just as effective as cytosine arahinoside in reducing cellular levels of 2'-deoxycylidylic acid.' Other modes of action include the inhibition of DNA-dependent DNA polymerase' II. and miscoding following incorporation into DNA and RNA."7 Cytosine arabinoside is readily transported into cells and phosphorylated by deoxycytidine kinase. It acts predominantly in the S phase of the cell cycle. Tumor cell resistance is based

on low levels of deoxycytidine kinase and the elaboration of deaniinases that convert cytosinc arabinoside into uridine

Partially purified cytidine deaminase is inhibited by tetrahydrouridine.''°

NH2

N

/ HO -

Cylarabine (Cytosine arabinoside) HO

Ancilab,ne (CyCloCyildIfle)

OH

Capecitabine

Gemcitabine

A new analogue of cytosine urabinoside is cyclocytidine (ancitubine). This analogue apparently is a prodrug that is slowly converted into cytosine arahinoside. It is reported to

408

Wilson tind

of Organic Medicinal €nijl l-'/,ar,na(-e,aital Chemistry

F

C—F

II

H2NCH7CO2H

I O

II

HN

I

C—NHCH,CD.H -

H7NCH2CO.,H

HO TritIur,dine

tlnlluorothyrnldne)

HO

Scheme 12—8 • Reaction of trifluorothymidine with glycine.

be resistant to deamination and to have a better therapeutic index than the parent compound'21 A number of pyrimidine nucleosude analogues have one more or one less nitrogen in the heterocyclic ring. They are known as azapyrimidinc or deazapyrimidine nuclcosides. 5Azacytidinc was symhesized in 1964 by Sórm in Czechoslovakia'21 and later was isolated as an antibiotic by Hanka.'22 The mode of action of this compound is complex. involving anabolism to phosphate derivatives and deamination to 5azauridinc. In certain tumor systems. it is incolVorated into nucleic acids, which may result in One of its

main effects is the inhibition of orotidylate decarboxylase

for compounds that might inhibit these deaminases. In ory, a potent dea,ninase inhibitor would produce a tic effect on the antitumor activity of the antimctabolite.eser though it might not be active itself. Two types of

inhibitors have emerged recently. One type is the analogue in which the pyrimidine ring has been expanded

to a seven-membered ring. The first example of this was 2'-deoxycoli.rntycin (pentostatin). an unusual nudcs' side produced in the same cultures as the antibiotic (a

mycin.'26 It strongly synergized the action of against organisms that produce deaminases. In trials it showed a synergistic effect on the

4

(Scheme 12-9). which prevents the new synthesis of pyrimidine nucleotides.'24 Tumor resistance is based on decreased phosphorylation of the nucleoside. decreased incorporation into nucleic acids, and increased RNA and DNA polymerase

adenine arabinoside and cytosine arabinoside. A sectni type of adenosine deaminase inhibitor has the adeiiirv

Other pyrimidine nucleoside antagonists that have received clinical study include dihydro-5-azacytidine

site of the enzyme and take advantage of strong to adjacent lipophilic regions.'27 El-INA is an cxampk ii a rationally designed inhibitor.

and

portion unchanged but is modified in the ribose Such modifications have been designed to probe the ada

NH2

NH2

H OH

N

HO—CH,

HO—Cl-I?

0 HO OH HO AzacdOno

HO'' 2'.Deoxycotormycin

Resistance to purine and pyrirnidine antimetabolites, such as adenosine arahinoside and cytosinc arabinoside. by neoplastic cells that produce deaminases has stimulated a search

C6HI3CHCHCHa OH EHNA

After the discovery of folic acid, a number of based on its structure were synthesized and tested as

Chapter 12 • .4iiIineop!a.ctir A,,'eIit.l

409

0 Aspartoto Transcarbamylase

+

H7NOH C02H

NH2 CO2H

Carbamoylaspartic Acid

Carbarnoylphosphate

J

0

0

H20,P

0 NAD Dihydroorolale

HO

Dehydrogeriaso

OH

CO2H

CO2H Orolic Add

Ofotidyfrc Acid Decarboxylase

0

0 HN

NH2 Gkjtamino

H409P3

Uridine Tripliosphate

Acid

Cytidine Triptiosphale

Scheme 12—9 • De novo synthesis of pyrimidine nucleotides (simplified),

The N'°-methyl derivative of folic acid was found activity. Antitufinally was found for the 4-amino-4-deoxy deaminopterin. and its N '°-methyl homologue. metho-

an antagonist, but it had no anlitumor

(amethopterin).' CO2H

0

Foiic Acid

Methotrexate and related compounds inhibit the enzyme dihydrofolate reductase. They bind so tightly to it that their inhibition has been termed p,seudoirresersibh'. The basis of this binding strength is in the diaminopyrimidine ring, which is protonated at physiological pH. At pH 6. methotrexate binds stoichiometrically with dihydrofolate reductase (K, I 0 '°M). hut at higher pH the binding is weaker and competitive with the substrate.'2" Folate acid antagonists kill cells by inhibiting DNA synthesis in the S phase of the cell cycle. Thus, they are most effective in the logarithmic growth phase.'3° Their effect

on DNA synthesis results partially from the inhibition of CO2H

R

NR N

dihydrofolate reductase, which depletes the poo1 of tetrahydrofolic acid. Folic acid is reduced stepwise to dihydrofolic

acid and tetrahydrofolic acid, with dihydrofolic rcductase

Aminoplerin. R

Meihoirexalo.

R

H CH3

thought to catalyze both As shown in Scheme 1210. tetrahydrofolic acid accepts the f3 carbon atom of scrine. in a reaction requiring pyridoxal phosphate. to give N5.N'0methylene tetrahydrofolic acid. The last compound transfers

410

Wilso,, aiid

Textbook

of Organic Mt'dki,ial and F'harrnacewical CI,emi.orv

Reductase

Teirahydroloiic Acid

Dihydrolohc Acid

0 Thynsdylalo

R=

Syniholase

HOCH2CHCO2H

CO2H

Pyridoxal Phosphate

[

HN HN

5.1 O-Methenyltetrahydrofohc Acid

5.1 O-Meihyionotcirahydrotolic Acid

o

CHO

H 1 O.Forrnyitetrahydrotoiic Acid

5-Formyttelrahydrotohc Acid

Scheme 12—10 • Interconversioris of bk acid derivatives.

a methyl group to 2'-dcoxyuridylate to give thymidylate in a reaction catalyzed by thymidylate synthetase. Dihydrofolic

acid is generated in this reaction, and it must be reduced back to tetrahydmfolic acid beli)re another molecule of thymidylate can be synthesized. It is partly by their effect in limiting thymidylate synthesis that folic acid analogues prevent DNA synthesis and kill cells. This effect has been termed ihymineless death.'

The inhibition of dihydmiolate reductase produces other limitations on nucleic acid biosynthesis. Thus. N5.N'°-mcthylene letrahydmfolic acid is oxidized to the corresponding methenyl derivative, which gives N"-fomiyltctrahydrofolic acid on hydrolysis (Scheme 12-10). The latter compound is a formyl donor to 5-aminoimidazole-4-carboxanside ribonucleotide in the biosynthesis of purines.'3' N-Formyltetrahydrofolic acid, also known as leucovorin and citrovorum factor, is interconveruble with the N'°-formyl analogue by way of an isomerasc-catalyzed reaction. It carries the formimino group for the biosynthesis of formiminoglycine. a precursor

of purines (Scheme 12-6). Leucovorin is used in "rescue

therapy" with methotrexate. It prevents the lethal nlethotrexate on normal cells by overcoming the of tetrahydrofolic acid production. In addition, it inhihitsth active transport of methotrexate into cells and stimulates

efflux)° Recently, it was shown that giving thymidine with trexate to mice bearing Ll210 leukemia increased vival time. This finding contradicts the idea that ilwntia deficiency is the most lethal effect of niethotrexate on it mors. It suggests that the blockade of purinc might have greater effects on tumor cells than on cells.' Consequently, the administration of might protect the normal cells relative to the tumor cdl Unfortunately, the use of such thymidine rescue in clino trials was

Numerous compounds closely related to have been prepared and tested against neoplasms. structural variations, such as alkylation of the amino gncr partial reduction, and removal or relocation of nitrogens. lead to decreased activity. Piritrexim and ma

Chapter 12 • Antineoplaslie Agents

senate are analogues of methotrexate in which one or two nitrogens in the pyridinc ring are replaced by carbons, and the benzoyl glutumic acid chain is replaced by a more lipogroup. Like methotrexate, both compounds inhibit dihydrofolate reductase; however, they do not interact with the reduced folate transport system used by methotrexate. Consequently, they arc active in vitro against some forms of cnethotrexate resistance. Their increased lipophilicity allows npid transport by simple CH3O CH2

411

nutrient for normal cells, many tumors depend on exogenous sources of it. This provides a rationale for the selective action of agents that interfere with the uptake, biosynthesis, or func-

tions of glutamine. In 1954. azaserine was isolated from a Srre,nomvc'es species.'42 It was found to antagonize many of the metabolic processes involving glutamine, with the most important effect being the conversion of formyl glycine ribonucleotide into formyglycinamidine ribonucleotide (Scheme A related compound. 6-diazo-5-oxo-i-norleucine (DON), was isolated in 1956 and found to produce similar antago-

nism)" A study involving incubation with F'4Clazaserine followed by digestion with proteolytic enzymes and acid

CH2__->\

hydrolysis produced S-f "'Clcarboxymerhylcysteine, which showed that azaserinc had reacted covalently with a sulihydryl group of cysteine on the enzyme.'45 DON is a more potent inhibitor than azaserine of this enzyme and of the enzyme that converts uridine nucleosides into cytidine nucleosides."" Although both compounds show good antitumor activity in animal models, they have been generally disappointing in clinical trials.

Piritrexim

Produce Mercaptopurine, USP.

Tnmetrexate

Although the active sites of dihydrofolic reductases from and neopla.stic cells arc identical. Baker proposed u regions adjacent to the active sites of these enzymes

differ. He designed inhibitors to take advantage of differences, thus affording species specificity. One of inhibitors, known as "Baker's antifol." shows activity iaiust experimental tumors that are resistant to methoGluramine and glutamate arc the donors of the three- and

atoms of purines and the two-amino groups They also contribute the three-nitrogen atom he amino group of cytosine'4' (Schemes 12-6 and 12Thus, they axe involved at five different Sites of nucleic biosynthesis. Although glutamine is not an essential

Mercaptopurine, Purinethol, 6mercaptopurine. 6MP. Lcukcrin, Mercalcukin, NSC-755, 6punnethiol, is prepared b; treating hypoxanthine with phosphorus pentasulfide"'7 " and is obtained as yellow crystals of the monohydrate. Solubility in water is poor. It dissolves in dilute alkali but undergoes slow decomposition. Scored 50-mg tablets are supplied. The injectable formulation is in vials containing 500mg of the sodium salt of 6-mercaptopurime, which is reconstituted with 49.8 mL of Sterile Water

for Injection, liSP. Mercaptopurine is not active until it is unabolized to the phosphorylated nucleotide. In this form, it competes with endogenous ribonucleotides for enzymes that convert mosinic acid into adenine- and xanthine-based ribonucleotides.

Furthermore, it is incorporated into RNA. where it inhibits further RNA synthesis. One of its main rnetabolites is 6mcthylmcrcaptopurine ribonucleotide. which also is a potent inhibitor of the conversion of inosinic acid into purines.'48 Despite poor absorption, low bioavailability. and firstpass metabolism by the liver. mercaptopurine has oral activity. Peak plasma levels of about 70 ng/mL are reached I to

0 U

0 .

II

HO2CHCH2OCCHN2 + HSCH2CHCO— —p HO2CHCH2OCCH2SCH2CHCO—

NH—

NH2

NH—

NH2

Azaserine Hyd:otysis

0

0 N2CHC(CH2)z?HCO2H NH2 DON

NH2

412

and

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86(1. 21811.

SELECTED READING Dorr. K. I., atttd Von lioll, I), I).: Caticcr Chemotherapy Handbook. Nor walk. CT. Appleton & Lange. 1994. Fnye. W. 0. led.): Cancer Chernothcrapcutic Agents Washington. IX'. American Chemical Society. 1995. Hail. T. C. ted.): Prediction tiC Kcspttnse lit Cancer Chemotherapy. New York. Alan K. Liss. 1988. Hickman. J. A.. and Trittoit, 1. R.: Cancer Chenutther.tpy. Oxford. I)tackwell Scientific Publications. 1993. Kepplcr. B. K. lcd.): Metal Complexes in Cancer Cbetnotherampy. York, Wcinhcim. 1993. Oldhatm, R. K. led.): Principles oF Cancer Bit8herapv. New York. Raven Press. 1987.

Pined,,. II. M.. mind Giaccone. (4. teds.): Drug Resistance in die Trcalntetii olCunccr. Cantbridge. United Kittgdoitm. Caitnbridgc University Press. 1998.

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P7. Hamilton. S. Ii.. ci at.: Biochemistry 36:11873. 1977. P4.. Vilieelhouse. K. 'r.. ci a).: J. Am. Chem. Soc. 120:3621. 1998. I'9 Petty. P. J.. cliii.: 3. Med. Chew. 41:4873. 1998.

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475. Raiajcuak. >.I. Z.. ci at.: Proc. Nail. Acad. Sci. U. S. A. 89:11823, 992.

Press. 1997,

C

N

A

P

T

E

R

13

Agents for Diagnostic Imaging TIM B. HUNTER. 1. KENT WALSH, AND JACK N. HALL

Diagnostic imaging encompasses a group of techniques used in the diagnosis and treatment of disease. These techniques

often use chemical agents to improve the information pro-

vided in the imaging. This chapter is a discussion of the pharmacology, chemistry. and physics of those agents used in medical imaging. Medical imaging techniques often present less risk to patients than direct surgical visualization. Also, they often pro-

vide information or treatment methods that are simply not available by any other means. What these techniques have in common is that the information is often (but not always)

displayed as an image for interpretation by a physician trained to evaluate the meaning of the image in the context of pathophysiology. Also, all of the techniques use physical phenomena (electromagnetic radiation, ultrasonic waves) that cart pass through tissue to convey the internal infonnation necessary to create an image. From that point, the techniques of medial imaging diverge in their physical means. methods, and the information that they can provide. Medical imaging began with Roentgen's discovery of xrays in 1895, and it has been the domain of diagnostic radiology since then. In its earl iest days. the specialty of radiology used x-rays to produce images of the chest and skeleton. At the present time, diagnostic radiology uses ionizing radiation (x-rays), magnetic resonance imaging (MRI) techniques, radionuclides (nuclear medicine), and high-frequency sound

waves (ultrasound) to produce diagnostic images of the body. Today, radiologists and other physicians also use diagnostic imaging techniques to guide themselves in interventional procedures, such as organ biopsy or abscess drainage.

INTRODUCI1ON TO RADIATiON Radiation is the propagation of energy through space or mat-

ter. In chemical reactions, only the valence electrons of an atom are affected, and the nucleus remains unchanged. Nuclear reactions may result from bombardment of' a stable nucleus with high-energy particles or decomposition of an unstable nucleus. The nuclei of atoms are of two kinds: stable

and radioactive. Radioactive nuclei have more internal energy than nuclei with a stable arrangement of protons and

neutrons. They obtain stability by emitting energy in the form of particulate and electromagnetic radiation. Ionizing radiation is radiation that when interacting with matter can cause changes in the atomic or nuclear structure of matter. The first type of ionizing radiation is particulate, positron proton which includes alpha (a). beta (p). and neutron (n) particles. Radiation is energy in the form of kinetic energy and on the atomic scale is usually measured in electron volts (eV). By definition, an electron volt is the

454

energy needed to accelerate an electron across a potential difference of I volt. The second type of ionizing radiation is called electromagnetic radiation. Electromagnetic radia tion is an electric and magnetic disturbance that is propa. gated through space at the speed of light. This type of radii tion has no mass and is unaffected by either an electrical or magnetic field because it has no charge. These propeniet are shared radio waves (I0'° to l0" eV), microwaaet to 10-- eV), infrared (102 to I eV). visible light U to 2 eV), ultraviolet (2 to 100 eV). or x-rays and eV). The various forms of electromagndic rays (100 to radiation differ in their frequency and, therefore, their en ergy. The energy of electromagnetic radiation can be calcu

lated in electron volts from the following equation:

E=

=

eV-scc). where /t is Planck's constant (4.13 X the frequency (hertz). c is the speed of light (cmlscc), aid

A is the wavelength (cm). The difference between x-rays arid

y.rays is based on where they originate: x-rays come fore outside the nucleus, while y-ruys originate in the nucleusol

an atom. X-rays and y-rays can exhibit some paniculas properties, so they are sometimes called photons. Applying a very high voltage (20.000 to 150.000 to a glass vacuum tube that contains a cathode and a anode produces A-rays used in diagnostic radiology (Fig. Lt

I). The cathode is a filament that is heated to a veiy temperature, which provides a copious source of elcetroet The electrons are accelerated toward the positively chargal anode (tungsten). When the accelerated electrons strike Is anode (called the target), A-rays are produced. The tion of x-rays is a continuous spectrum, and the low-eneip

x-rays, which will not travel through the body to the a filter (aluminum). An invalualdi modification of the x-ray system is fluoroscopy. This ity allows one to visualize organs in motion, positiou ft patient for spot film exposures. instill contrast media ia hollow cavities, and, most importantly, insert catheters it arteries. Figure 13-2 shows a schematic of a system.

With conventional radiography and with computed mography (CT) (sometimes called computed axial phy ICATI) scanning, organs and tissues are made according to how well they attenuate x-rays. The attcnualia of x-rays by tissues is a complex process that depends a many factors, including the energy of the x-ray beam aid the density of the tissue. Bone has an average densit) 0 about 1.16 g/cm3, which accounts for its ability ta alan most of the radiation it encounters. CT scanning (Fig. 3) uses ordinary x-ray energies for imaging but uses cornidt

Chapter 13 • Agenca for Diag,ws:ic Imaging

455

ommendation of the International Union of Pure and Applied

Chemistry, the following notation should be used for the identification of a nuclide: Example:

where X is the symbol of the chemical element to which the nuclide belongs. A represents the atomic mass (number of neutrons plus the number of protons), and Z represents the

atomic number (number of protons). The right side of the element is reserved for the oxidation state, and N represents

the number of neutrons. For most medical applications, it suffices to indicate the element chemical symbol and the mass number (i.e.. 1311, 1-131. or iodinc-13l). The radionuclide at the beginning of' the decay sequence is referred to as the parent, and the radionuclide produced

by the decay is referred to as the daughter, which may be stable or radioactive. There are five types of radioactive decay, distinguished according to the nature of the primary radiation event. A radioactive nucleus may decay by more than one method. The dominant method at any given time depends on such factors as the size of the nucleus and the balance of protons and neutrons. The types of decay described below are in order of how commonly they are used in current diagnostic nuclear medicine practice:

-9

Film

1. Isomerlc transition (IT). Isomeric transition is a decay process involving neither the emission nor the capture of a particle. The nucleus simply changes from a higher to a lower energy level by emitting y'rays. Therefore, both mass number and atomic

rigure 13—1 • Schematic diagram of an x-ray tube producing

that pass through the patient and expose the photogiaphic film. The photographic film will not stop the x-rays. a a plastic screen coated with fluorescent particles that are by the x-rays emits light to expose the film within a

TV Monitor, V,deo System

film cassette. As x-rays pass through the body, some ci them are scattered, so a moving grid device composed of altemaling strips of lead and plastic decreases the scattered xrays that degrade the image.

reconstructions to produce images of the body it the axial and other planes. In the process, it can increase lie visibility of small differences in the radiographic dcnsi-

between tissues to a far greater extent than ordinary adlographic film can.

undergoing transformation processes. ailed radioactive decay, in most cases involve transmutaion of one element into another. A nucleus may undergo decays before reaching a stable configuration. A nu-

Optical System

Radionuclides

Image Intensifier

dearparticle, either a proton or a neutron, is called a nucleon. A igecies of atom with a specified number of neutrons and

in its nucleus is called a nuclide. Nuclides with the oar number of protons and a different number of neutrons ne called isotopes. Nuclides with same atomic mass are oiled isobars. Nuclides with the same number of protons codatomic mass but at two energy levels are called iso,ners.

The nucleus has energy levels analogous to the orbital ileciron shells but at a higher energy. The lower energy level

i.called the ground (g) state, and the highest energy level called the metasiable (m) state. Nuclides are all species if elements, of which there are about 265 stable nuclides, 331) naturally occurring radionuclides. and more than 2,500 sliticially produced radionuclides. In accordance with a rec-

Screen

X-ray Tube

Figure 13—2 • Schematic diagram of a fluoroscopic unit with the x-ray tube located behind the patient and a fluorescent screen—image intensifier system positioned on the opposite side. Amplification of the faint fluorescing image by the image intensifier increases brightness level and contrast. The real-time fluoroscopic images can be shown on a television camera for

convenient viewing during the examination and stored on videotape, video disk, or computer for later viewing without distortion or destruction of the images.

456

Wilson and Gi.si'old's Texlho,,k of Organic Medicinal and J'hannaeeutital Che,ni.t try

Original Image Reconstruction

E= where in the case of an electron. E represents energy cquivalcs:

to mass (,n = 9.109 X 10" kg) at rest, and e is the speed of light (3 x rn/see). By using the proper units it can be shown. that the mass of an electron is equivalent 100.511 MeV. called annthila,ion radiation. It is used in a specialized imaoinf technique called ,io.sirron emission U'ETI.

+ v-ray

Example:

fir + e —2y-rayslO.5Il Mcvi 4. Beta-partIcle emission fifl. The nucleus emits a negative eke. Iron when a ncuirotl changes to a proton. A y-ruy may or not accompany the emission of a fi particle.

+ ir + v-ray

Example:

5. Alpha-particle emission (a). The nucleus emits an a pattklc which consists of a helium nucleus without the clectroni. 11th: emission of the a particle leases the nucleus in an excited state, the excess energy is liberated in the tirm of a v-ray, Example:

+

+ v-ray

CHARACTERISTICS OF DECAY It is impossible to predict when an individual atom ui: radionuclide will decay. In quantitative terms, however. thi.

transformation occurs at a rate that is characteristic of specific radionuclide and is expressed as its physical life, This is the time in which one-half of the original numlst of atoms decay. The activity of radionuclides can be ci pressed in three ways: (a) in curies I Ci). tnillicuries(rnfi.

Radiation Detectors Figure 13—3 • Schematic diagram of a computerized axial tomography (CAT) system that produces thin cross-sectional im-

ages of the body. An x-ray tube rotates around the patient, and lhe transmitted s-rays are detected by a circle of moving radiation detectors. The absorptions of x-rays by tissues of dit' ferent densities are assigned numerical values (CT numbers). The computer uses complex algorithms to reconstruct an anatomical cross-sectional image on a television monitor.

or microcuries (1aCi): (h) in disintegrations per second (dpiJ and (c) in becquerels (13q: I Bq = I dps). A curie is lit

quanhity of any radionstclide that decays at a rate of 3,7'

lOin dps. This number was chosen for a hishorical rn son—this is the number of disintegrations per second in g of radium. The international systent of Units has adupini the beequerel us the official Unit of radioactivity. but lv curie is still widely used, and we will use this unit iii additsi to the official unit. A relevant conversion facior to remembr

is the lollowing: number remain unchanged. The daughter nucleus is the same chemical element as the original nucleus. The original nucleus betore the transition is said to be in a metastable (ml state. Example:

+ y-ray

2. Fiectron capture decay fEC). The nucleus captures an electron

I

millicuric lntCi) = 37 megabeqtterels (MUg)

The basic equation for radioactive decay is cxprcssedn.

follows in terms of atoms:

N, = N, e1'

from thc electron cloud of the atom (mainly the K shell), and a proton becomes a neutron. Example:

pai/i v-ray

The nucleus emits a positive electron 3. Positron emission when a proton changes to a neutron. A v-ray may or may not accompany the emission of the positron. A positron (particle of antimatter) emitted from the nucleus loses its kinetic energy. however, by interacting with surrounding atoms. It finally combines with a free electron from one of the surrounding atoms in an interaction in which the rest masses of both particles are given up as 2 v-rays of 0.511 McV emitted at 180° to each other. Einstein's theoty of relativity states that macs and energy arc equivalent and is represented by the following equation:

N, (number of atoms at time I) and N0 (number of alor at time 0) can be replaced, however, with activities: A, = .4,,

Ar

where A11 is the original activity in Ci. mCi. or PCi, the ttctivity at time :. A is the decay constant (= 0.6931i,. the physical half-life); and is the decay factor. Ancsrn pIe of a radioactive decay calculahion follows: A sample of iodide had an activity of 200 jzC' U May 14 at 12 noon C.S.T. What is the activity on May 1St E.S.T.? (Note: Calculations of elapsed time must also

Chapter 13 • Agenl.c fur Diagnasth' Imaging

457

indicate variations in time zones—elapsed time in this case is

the indirect effect, involves aqueous free radicals u.s interme-

26 hours)

diaries in the transfer of radiation energy to the biological = 13.2 hours) A =

10.693 X 26 hours' 13.2 hours

2(X)

"L

]

A = (200

fr-I

A = (2(M)

(0.255)

A = 51.0 /2Ci

BIOLOGICAL EFFECTS OF RADIATION The absorption of ionizing radiation by living cells always iwduces effects potentially harmful to the irradiated organnm. An undesirable aspect to the medical use of these types

(radiation is that a small number of the atoms in the body will have electrons removed as a result of the energies ef these photons. Radiation that does this is often called :wii:ing radiatio,, and is damaging to body tissues. Therein using ionizing radiation, as in using other pharmaagents, the risks must be balanced with the medical provided for the patient.

The amount of radiation energy absorbed by tissue is absorbed dow and is specified in rude or sillirads. A dose of I rad implies 100 ergs ol energy abper gram of any tissue. The unit of exposure for xtl)5 and y radiation in air, the roentgen, is used to specify cidbtion levels in the environment. (One roentgen is the aaunt of radiation that produces I electrostatic unit of iharge of either sign per 0,001293 g of air at STP.) The ailed radzatwn

system of Units (SI) has adopted the gray (Gy) the

(I Gy = 1(X) rads). but again we will use

)icmoretraditionul units. In the case of x-raysor yradiation medical diagnosis, the roentgen and rad turn out to be rsmerically equivalent. The major difference between eleccumagnetic radiation (x-rays or y-rays) and particulate type a particles) lies in the ability of electromagretic rays to penetrate matter. Whereas fi particles travel no a few millimeters before expending all their energy. xdistribute their energy more diffusely and travel nJ several centimeters of tissue. Therefore, particles kliver highly localized radiation doses, whereas x- and yins deliver more uniform doses in a less concentrated way 'broughoul the irradiated volume of tissue. The radiation .be of particles is more useful for a therapeutic dose of a idionuclide but not for a diagnostic dose. When cells are icidiated. damage is produced primarily by ionization and

molecules. All biological systems contain water as the most abundant molecule (70 to 90%). and radiolysis of water is the most likely event in the initiation of biological damage. The absorption of energy by a water molecule results in the ejection of an electron with the formation of a free radical ion (H20 ' ). The free radical ion dissociates to yield a hydrogen ion and a hydroxyl free radical (HO). The hydroxyl free radicals combine to form hydrogen peroxide (H202). which is an oxidizing agent. In addition, hydrogen free radicals (H can form, which can combine with oxygen (02) and form a hydroperoxy-free radical (HO2). These two reaction intermediates are very reactive chemically and can attack and alter chemical bonds. The only signiimcant "target" molecule for biological damage is DNA. Types of DNA damage include single- and double-chain breakage, and intermolecular or intramolecular cross-linking in the doublestranded DNA ntolecule. With the direct effect of radiation. the damage makes cell replication impossible, and cell death

occurs. In the indirect effect of radiation, if the damage is not lethal but changes the genetic sequence or structure, mutations occur that may lead to cancer or birth of genetically damaged offspring. Some effects of radiation may develop within a few hours: others ntay take years to become apparent. Consequently, the effects of ionizing radiation on human beings may be classified as somatic (affecting the irradiated person) or genetic (affecting progeny). Radiation dose can only be estimated and its "measurement'' is called radiation dosimetry. In the case of x—ray

exposure. most radiation "doses" in the literature are described as the entrance exposure (in rocntgcns per minute) to the patient. In diagnostic nuclear medicine procedures. patients are irntdiated by radiopharmaceuticals localized in certain organs or distributed throughout their bodies. Since the radionuclides are taken internally, there are mummy variables. and the radiation absorbed dose (r.a.d. or mdl to indi-

vidual patients cannot be measured hut only estimated by calculation. The methods of calculating the absorbed dose to patients from radiopharmaceuticals were changed in 1964 and then revised by the Medical Internal Radiation Dose

(MIRD) Committee under the auspices of the Society of Nuclear Medicinc in 1991. Although the effects of radiation arc not totally understood, the benetits associated with low doses of radiation almost always outweigh any potential risks to individual patients. A large number of scientific and advisory groups have published risk estimates for ionizing radiation, but the most widely quoted is report number 5 of the National Academy of Sciences Committee on the Hiological Effects of Ionizing

're

radicals. Particles produce damage by ionization. produce damage by free radicals. hereas x-rays and

Radiation (BEIR-V).' Under normal circumstances, no radiation worker or patient undergoing diagnostic investigation by radiopharma-

free radicals are atoms or molecules with an unpaired elec-

ceutical or radiographic procedures should ever suffer from

inn.

effects of large doses of radiation were derived from studies of the atomic bomb survivors at Hi"hima and Nagasaki. Radiohiologieal damage from large lies of ionizing radiation can be caused by two different One mechanism is the direct effect of radiation. The

rwhich damage results front absorption of radiation energy in a critical biological site or target. The other, called

any acute or long-term injury. Typical radiation doses to patients from radiophannaceuticals are similar to. or less than, those from radiographic procedures. The tim-st artificial radionuclide (phosphorus-30) was produced by the French radiochemists Frederic Joliet and Irene Curie. Nuclear medicine became a specialty in 1946 when radionuclides became available front cyclotrons and nuclear reactors. In many medical centers, nuclear medicine is con-

458

Wil.con and Gisvold.c Textbook of Organic Medicinal and Pharmaceutical Chemi.ctrv

sidered part of diagnostic radiology, although in some lo-

1V Monftor

cales it may be a freestanding discipline or reside in a pathology or intemal medicine department.

RADIONUCLIDES AND RADIOPHARMACEUTICALS FOR ORGAN IMAGING

Computer

Medical science provides a framework or paradigm in which to understand disease and to maintain health. Nuclear medicine is the branch ol medical science that contributes to medicine by the use of the radiotracer method for diagnosis and

use of in vivo unsealed radioactivity for therapy. Nuclear tnedicine involves the administration of radioactively labeled compounds to trace a biological process. This process may be mechanical (gastric emptying, blood flow. cardiac wall motion) or a variety of other physiological functions. Within the concept of a 'radiotracer" is the implication that the agent administered will not disturb the function-

PM Tubes

Nat Cyst&

ing of the process you wish to examine. In nuclear medicine, this concept is used to trace physiological processes in vivo and then compare them 10 known normal images or levels. These are then evaluated with a knowledge of pathophysiology to allow diagnosis of disease. The data can also be used

to follow the patient for improvement after treatment. In clinical practice, nuclear medicine also makes use of in vitro diagnostic methods (radioimmunoassay) and in vivo radiopharmaceutical therapy. These last two are not further addressed in this chapter, and there is minimal discussion of investigational diagnostic radiotracers, The specialty of nuclear medicine did not become available to the private hospital until the l960s. after the introduction of the molybdenum-99hechnetium-99m generator and the gamma (scintillation) camera developed by Hal Anger (Fig. 13-4). The most common use of nuclear medicine is to image the distribution of radiopharmaceuticals in specific tissues or organ systems with a scintillation (Anger) camera for diagnostic purposes. Fundamentally, these instruments or cameras allow in vivo detection and localization of radiotracers. The purpose of the gamma camera is to record the

location and intensity of the radiation within the imaging field. Radiation in the form of gamma photons (occasionally x-

rays) initially enters the camera through the collimator.

Lead Cofllmator 'v-rays

Figure 13—4 • Schematic diagram of scintillation camera (Anger) system with a multihole lead collimator attached eliminate scattered v-rays), which is used to visualize tissuer and organs after a diagnostic dose of a radiopharmaceuricaf administered.

video monitor. The images obtained with the scintillailor camera are called scintigrams. scintigraphs. or scans. No clear medicine imaging studies involve the generation ul images that represent the functional status of various argue in the body. Especially when interfaced with tems, information regarding dynamic physiological pasuim eters such as organ perfusion, metabolism, excretion, ani the presence or absence of obstruction can be obtained. Fiç ure 13-5 demonstrates a norma! dynamic function stud) ci

the liver, made by using Tc-99m mebrofenin and the lation camera. Images can be acquired of one organ or

the whole body by moving from head to toe.

made holes. It covers the detector crystal. The purpose of

Cross-sectional images of organs can be obtained by ing a position-sensitive scintillation camera detector abet the patient. This type of procedure is called single plot"

the collimator is to decrease scattered radiation and increase

emission computed tomography (SPECT). which is tlte caio

the overall resolution of the system. Photons that are not blocked by the collimator then enter a large sodium iodide (with a small amount of thallium) crystal that absorbs v-

crystal are photomultiplier (PM) tubes that convert the tight

terpart of CF or CAT scans in diagnostic radiology. Fifr: 13-6 is a schematic of a SPEC!' system. The majority i SPECF systems use one to three scintillation camera tore that rotate about the patient. SPEC!' is routinely when imaging the brain or heart to demonstrate sional distribution of radioactivity in these organs. Figm 13-7 depicts a SPECT myocardial perfusion scan of th:

flashes to electrical pulses proportional to the amount of

heart.

tight. To localize the original source of the photon (and create an image), a computer assigns x—y spatial coordinates to the various v-rays coming from the patient and stores this information in a matrix. After collection, the digital image is converted into an analogue video signal for display on a

A newer modality for imaging uses multiple dctccs.r heads to image positron-emitting

which usually is a sheet of lead with multiple small, precisely

rays. The absorbed energy in the crystal is emitted as a flash

of light (called a scintillation), which is proportional to the

energy of the v-ray. Coupled to the back of the Nal(Tl)

PET (Fig. 13-8). Many biologically important moleculestlit are physiologically identical with the nonradioactivc coc pound can be radiolabeled with positron-emitting radioc;

Chapter 13 • Agents for Diagnoslic Imaging

459

Figure 13—5 • Dynamic study of the liver and biliary system with a gamma camera. This is a normal study after injection of Tc99m mebrofenin, with each image a 3-minute time exposure. The study was done on a patient with suspected acute cholecystitis (a blockage of the duct to the gallbladder) If the patient had acute cholecystitis, the radiotracer would not have entered the gallbladder. The arrow in frame 16 shows the normal location of the gallbladder. TV Monitor

,— Computer

Figure 13-6 • Schematic diagram of a rotating triple-detector scintillation camera system for single photon emission computed tomography (SPECT) demonstrating a "cold spot lesion in the brain on the sagittal view (open arrow).

460

Wi/sc,,: and (Ji.cvold s Texthook of Organic Medicinal cnn! l3lusnnacns:ical Chemtc:rv —.,--

—

-

—a—-

9 ç) 4,

F

1

--

IF —

Ap?!

Figure 13—7 • SPECT myocardial perfusion study using thallium-201 as the radiotracer, SPECT images are

three-dimensional and are often viewed in tomographic slices. The long arrows indicate the abnormally diminished myocardial perfusion in the anterior wall of the left ventricle during stress (exercise or logical), compared with that of the same patient during rest. The stress and rest images are matched in spatial location for easier comparison The single short arrow indicates an additional abnormal area in the

inferior portion of the left ventricle. The abnormalities indicate that the patient has a high likelihood of significant coronary artery narrowing, which can be confirmed by coronary angiography.

TABLE 13-1 PET Radiotracers

Positron Emitter TV Monilor

Raóabon

Fluorine- 18 (F•IS)

Radiotracer F- i 8iialoperidol F- i S Ilunmdecixyglucocc (I•Th1

F-IS flunrodopa

F I K flurueihylspipcronc

/ 1'

F-18 flunrouracil

I L.Corp,jtor

Niirogcn-13 (N-i 3)

N-li ammonia

Carbon-I I

C-Il Acetate

C-I I curfenianil

C-il cocaine C-Il Depranyl C-li kucine Figure 13—8 • Schematic diagram of a PET imaging system with multiple scintillation detectors that localize the positron decay along a line. By using multiple position-sensitive detectors around the patient, the annihilation photons are acquired along many parallel lines and many angles simultaneously with four rings of detectors (only one ring shown). After use of reconstruction algorithms, the internal distribution of the radioactivity can be determined and displayed on a cathode ray tube.

Oxygen 15

inedlion

C-Il

niethyispipemne

C-I 1 racloprlde 0-15 waler

0-15 0.1$ Rubidiu in -1(2

lilt

C- 11

oxygen carbon

Rubidiuni.$2

dioxide

Chapter 13 • Agents for Diagnostic Imaging

461

1'

FIgure 13—9 a PET whole-body images performed to detect metastases after injection of 4 mCi (148 M8q) of fluorine f '8FJ-2 -f luoro-2 -deoxy-o-glucose (F-i 8 fDG). A. Normal whole-body PET image (coronal view) obtained on a patient with lymphoma after treatment

with chemotherapy and radiotherapy.

4

The patient fasted for 12 hours to ma intam the blood glucose level between 80

and 140 mg/i 00 ml. If the blood glucose level is not in that range, F- 18 FDG

uptake is decreased in the tumors because the mechanism of uptake is an increased rate of glycolysis. (Note increased brain and cardiac uptake because of high glycolytic rates in these organs.) B. PET whole-body image tamed with the same technique on a patient with pancreatic carcinoma. Abnormal sites of F-18 FDG uptake are seen in the upper abdomen, posterior mediastinum, and left lower neck (ar-

S

rows) consistent with neoplastic in-

S

volvement. (Note increased brain, but not cardiac, uptake of F-18 FDG in this patient who had a desirable blood glucose level for tumor imaging.)

B

dides such as carbon-Il (:in = 2 minutes), nitrogen- 13 (tic

20 minutes), oxygen-S (,a

where Cd- 1 1 2 is the stable target material, a proton (p) is

10 minutes). and fluorine-

the bombaSing particle. two neutrons (2n) are emitted from Uie nucleus, and In- 1 I 1 is the radionuclide produced. The introduction of radionuclide generators into nuclear medicine arose from the need to administer large doses of

= 110 minutes). Table 13-I shows examples of several positron radiouacers that have been investigated in iS Ku?

'it scientific literature. Figure 13-9 shows PET whole-body images from patients cancer management modality. -

PRODUCtION The radionuclides used in nuclear medicine are artificially This is accomplished when neutrons. protons. a

or other particles impinge on atomic nuclei and üntiate a process of nuclear change. The artificial production

(a indionuclide requires preparation of a target system. indiation of the target, and chemical separation of the radio:aclide produced from the target material. The radiochemiJisconvcrted to the desired radiopharmaceutical and qualassurance of the physical. chemical, and pharmaceutical

(i.e., sterility and apyrogenicity) of the final product s obtained.

The systems used for practical production of

rilionuclides are a nuclear reactor, cyclotron, or radioisogenerator.

The shorthand nuclear physics notation of a cyclotron proiicdon reaction is as follows:

(p.2n)'U

Zn

a short half-life radionuclide to obtain better statistics in imaging. in consideration of radioactive (parent and daughter) pLLIrS. we can distinguish two general cases, depending on which of two radionuclides has the longer half-life, lithe parent has a longer half-life than the daughter, a state of so-

called radioactive equilibrium is reached. Thai is. after a certain time, the ratio of the disintegration rates of parent and daughter become constant. in the second case, if the

parent half-life is shorter than that of the daughter. no equilibrium is reached at any time. Therefore. the general principle of the radionuclide generator is that the longerlived parent is bound to some adsorbent material in a chromatographic ion exchange column and the daughter is eluted from the column with some solvent or gas. There are more

than 100 possible generator systems for clinical use, but there is only one in routine use in nuclear medicine (the molybdenum-99/technetium-99m system). All of the molybdenum-99 at the present time is obtained as a fission product

of uranium-235 in a nuclear reactor. (n, fission) —4'Mo ÷ other radionuctides

By use of elegant inorganic radiochcmistry, the molybdenum-99 is separated from the other radionuclides. Molybde-

462

Wilson and GisrokFs Texthook of Organic Medicinal and Pharmaceutical Chemistry

0.9% NaO (Sterile)

3O•mL

Evacuated Vial

shield

rlc-99m pertechnalale In 09%

NaQ

---Elutlon needle

Airway needle with —% bacteriological fitter

bacterloloØc& fiRer

Injection port for loading

Mo-9øon the column by manufacturer Stainless steel fluid paths

—Mo.99 adsorbed

onaluminasnion exchange coluni '—Lead shield

Figure 13—10 • Cross section of a radionuclide generator for the production of technetium-99m fTc•99rn) by sterile 0.9% sodium chloride elution of a sterile alumina (Al,03) col-

umn that has molybdenum-99 (Mo-99) adsorbed on it. (Courtesy of Dupont—Pharma, Billerica, MA.)

num-99 = 66 hours) decays by fl-particle emission to tcchnctium-99rn = 6 hours), which dccays by isomeric transition (IT) to technctium-99 by emission of a y-ray (140 2) keV). The anionic molybdate is then loaded on a

column of alumina (Fig. 13-10). The molybdate ions adsorb firmly to the alumina, and the generator column is autoclaved to sterilize the system. Then the rest of the generator is assembled under aseptic conditions into its final form in a lead-shielded container. Each generator is eluted with sterile

1.0

normal saline (0.9% sodium chloride). The column is an inorganic ion exchange column, and the cluate contains so-

0.5

dium pertechnetatc. so the chloride ions (Cli are exchangbut not molybdate

ing for the pertechnelate ions

ions (MoOf2). The method for calculating how much daughter is present on the column at any given time is more complex. because it must consider the decay rates of the parent and daughter (Fig. 13-11). The simplified equation for any case in which both the parent and the daughter are

Mo-99 Mmdmum = S6hours

I 0.2

radioactive and in equilibrium is as follows: =

l(r"

cs

— 431

where A,, is the activity (mCi) of the parent. A1, is the activity are their respective decay conof the daughter. A1, and stants. and us the time since the last elulion of the generator. In the case of Mo-99 = 66 hours, only 87.2% of the

atoms decay to Tc-99m (in = 6 hours), and 12.8% 1)1 the atoms decay directly to Tc-99. The generator system can be

cluted several limes per day to obtain more activity (mCi) per day because the increase in Tc-99m is a logarithmic function.

Hours

Figure 13—11 • Elution graph of radioactivity versus time (linear) of the Mo-99rn/Tc-99m tor with sterile 0.9% sodium chlorcde for 2 days (actual gerew tor is useful for 12 days posicalibratcon). The upper straight br-: represents the radioactive decay of the parent (Mo-99) to iF; daughter (Tc-99m), which reaches equilibrium at four

of the daughter (6 hours x 4 = 24 hours).

Chapter 13 • Agess:s fir Diagnostic Imaging

TECHNETIUM RADIOCHEMISTRY Element 43 in the periodic table, technetium, is a transition state metal and is the only 'artificial" element with a lower

atomic number than uranium. All 22 known isotopes of technecium ant radioactive, and there are eight nuclear isomers. Because no stable isotopes of technetium exist, the chemistry has been poorly developed; however. milligram quantities years) u(Tc-99 (a weak fl-particle emitter; = 2.1 x arc now available for determination of the structures of the technetium complexes. and more than ISO structures have

characteri,ed. The chemistry of technetium is similar to that of rhenium and is dominated by forming compounds by bonding between the electron-deficient metal and electro-

groups.. which are capable of donating electron pairs. Some examples of these electronegative groups are suilbydryl. carboxylic acid, amine, phosphate. oxime. hydronyl. phosphinc. and isonitrile. Basically, all technetium radiophurmaceuticuls are metal—electron donor complexes. Compounds that contain so or more electron donor groups and bind to a metal arc ailed chelating agent.s. Technetium usa transition state element can have oxidation states from I to + 7. As a pertechion, technetium will not form many netate l1'c041 metal—donor complexes. although it can be reduced to spethat will complex with a variety of monodentate, hidenLate. or polydentate ligands. The oxidation state of techne-

rtrn in various complexes and the actual structure are ntknown for several ot the compounds. Deutsch Ct al.2 claim that the oxidation states that ant most common in the chemis-

irvoftechnetiumare + I, +3,nnd +5.Teehnetium(TcO1) an be reduced by a sttrnnous salt, ascorbic acid. sodium kmohydride. and electrolysis. The most common reducing is the sannous ion because of water solubility, stabilty. low toxicity, and effectiveness at room Resiews of the chemistry of technetium are presented by Hjclctuen4 and Schwochau,5 hut the stereochemistry of the inehnetium coordination complexes is not shown. An excelkni review by Jurisson et covers all coordination cornpsnnds used in nuclear medicine, with a special emphasis in Tc-99m complexes.

Tc-99m radiopharmaceuticals are by far the most cornused radiotracers in day-to-day diagnostic nuclear most gamma cameras are demedicine practice. In

to work most efficiently (crystal thickness and the with Tc-99m—based radiotracers. Tc-99rn radioare prepared at the hospital or local nuclear nonradioactive compo1unnacy by combining tents in a sterile serum reaction vial. The primary chemical .ubsianccs in the vial are the complexing agent (ligand) and mincing agent, usually some stannous salt (stannous chinstunnous fluoride, or stunnous tartrate). After prcparaeon of the radiopharmaceutical. tests for radiochemical puitv should be carried out to ensure that the radiotracer is in form. The analytical methods used include and thin-layer chromatography, column chromatograsolvent extraction. Likely radiochemical impurities some insoluble sodium pertechnetate

(i.e.. reduced hydrolyzed technetium tTcO2I or 4hnetium—tin colloid). and a complex different from the rather than °'5"Tcme especicd (i.e..

463

bidentate ligand). The sterile serum vials containing the Stannous salt and the ligand are lyophilized tinder a sterile inert

gas atmosphere (i.e.. nitrogen or argon). The ligand in the reaction vial determines the final chemical structure of the and the biological fate after intravenous injection of the radiopharmaccuticul.

Technethun Radiopharmaceuticals Albumin Injection. albumin for injection is a sterile, colorless to pale yellow solution containing human albumin (MW radinlubeled with Tc-99rn pertechnetate. The reducing agent is stannous tarnrate. which reduces the to an unknown oxidation state and is weakly chelated by the tartrate and possibly forms a complex with sulfisydryl groups on the albumin by ligand exchange. The precise structure of the stannous technetium—albumin complex is currently unknown. The patient Technetium

receives an intravenous injection of 25 mCi (925 Mug) of Tc-99m albumin. Multiple images of the blood in the heart are taken by electrocardiogram gating (R-R interval). The rising portion of the R wave coincides with end-diastolc. These images are stored in a computer to reconstruct a movie of the beating hean. This procedure is sometimes called a ,nul:igaied acquisition (MUGA) or a radionuclide r'enlruulogram. Information obtained by this technique includes cardiac chamber wall motion and calculation of ejection fraction. Indications for the procedure include evaluation of effects of coronary artery disease, follow-up of coronary artery bypass graft patients. heart failure, heart transplant evaluation (preoperative of cardiand postoperative). cardiomyopathies. and

otoxic drugs (i.e.. doxorubicin).

""ic-alTechnetium Aggregated. bumin aggregated is a sterile white suspension of human albumin aggregates formed by denaturing human albumin by heating at 80°C at pH 4.8 (isuelectric point of albumin). The precise structure of the stannous technetium—albumin aggregated complex is unknown at this time. The particle size and number can he estimated with a hcmocytometcr grid. The particle size of the suspension should he between This 10 and 100 gem. with no particles greater than 150 agent is used clinically to image the pulmonary microeirculation for pulmonary embolus and to assess regional pulmonary function for surgery (i.e.. lung transplants or resection). The patient receives an intravenous injection of 2 to 4 mCi (74 to 148 M13q) of the Tc-99m—albumin aggregates. which lodge in some of the small pulmonary arterioles and capillaries, and the distribution can be imaged. The number olaggre-

gates recommended for good image quality and is 100,000 to 500.0(8) particles: thus, only a small fraction of the 280 billion capillaries are occluded. Multiple images of the lung are obtained to assess lung perftision. The distribu-

lion of the particles in the lung is a function of regional blood flow; consequently. in the normal lung, the particles are distributed uniformly throughout the lung. When blood

flow is occluded because of einholi. multiple segmental "cold" (decreased radioactivity) defects are seen. This pro-

cedure is almost always combined with a xenon-l33 gas lung ventilation scan (should be normal in pulmonary ejinbo-

horn) and same-day chest radiograph x-ray (should be normal).

464

WiLton

and

Tethnetium

Textbook

of Qrxanic Medicinal and Pharmaceutical Che,nis:rv

Albumin

colloid

Injection.

"Tc—albumin colloid injection is a sterile, opalescent, colorless dispersion of colloidal human albumin labeled with Tc-99m pertechnetate after it is reduced with a slannous salt.

The precise structure of the stannous technetium—albumin colloid complex is unknown at this time. The particle size may be examined with a hemocytomcter grid. The particle size range of the colloid is 0.1 to 5.0 Alter the patient

receives an intravenous injection of 5 mCi (185 MBq) of Tc-99m —albumin colloid. the agent is cleared from the blood

by the reticuloendothelial (RE) cells. These RE cells are located principally in the liver (85%) and spleen (10%), and the remainder are in the bone marrow, kidney, and lung. An

initial dynamic flow study may be obtained to determine liver and spleen perfusion in cases of abdominal trauma. Liver and spleen imaging is useful to determine organ size. the presence of hepatic meta.stases. and the degree of hepato-

cellular dysfunction in diffuse liver disease (i.e.. cirrhosis).

Technetium Apcit!de. This new radiotracer is a synthetic peptide that binds to the GPllbIllla adhesion-

peptide with high-affinity binding to somatostatin recepton (subtypes 2, 3, and 5) present in many types of cancer. including lung cancer. Ii is approved for use in patients who are known to have, or are highly suspect for. malignanc) and exhibit pulmonary lesions on CT and/or chest x-zay. Over 170,000 new cases of lung cancer are diagnosed each year in the United States alone, and the alternative methods for determining malignancy are needle biopsy, which has as

estimated 15% complication rate, and surgery. The precise structure is cyclo-(L-homocysteinyl-N-meth. yl-L-phenylalanyl-L-tyrosyl-D-tryplophyl-L-lysyl-L-valyl). (1.1 ')-sulflde with 3-E(mercaptoacetyl)amino]-L-alanyl.L. lysyl-L-cysteinyl-L-lysinamide. A technetium Tc-99m com• plex of depreotide is formed when sterile, nonpyrogenic so. dium pertechnetate Tc-99m (15 to 20 mCi) injection. sodium chloride is added to a nonpyrogenic lyophilized mit ture of 50 of depreotide. sodium glucoheptonate dihydrate, stannous chloride dihydrate, 100 jcg of edetate disu dium dihydrate, and enough sodium hydroxide or hydrochloric acid to adjust the pH to 7.4 prior to lyophiliot tion.

molecule receptors found on activated platelets. This allows the detection of acute venous thrombosis and is Food and Drug Administration (FDA)-npproved for detection of acute

CH31

lower extremity deep venous thrombosis. A lyophilized preparation of 100 of bibapcitide in the presence of heat will split and then complex to 20 mCi Tc-99m pertechnetate. Images of area of concern are acquired at 10 and 60 minutes.

Technetium

Bicisate Injection. A sterile colorless solution of bicisate is complexed with Tc-99m pertechnetate after reduction with a stannous salt. The precise structure of the technetium complex is [N,N'-ethylene-di-Lcysteinato(3-)joxo diethyl ester. This radiopharmaceutical is a neutral and lipophilic complex that crosses the blood—brain barrier and is selectively retained in the brain. Therefore, this radiotracer is used as a brainperfusion imaging agent. After intravenous injection of 20 mCi (740 MBq) of Tc-99m bicisate, about 5% of the injected dose is localized within the brain cells 5 minutes after injec-

tion and demonstrates rapid renal excretion (74% in 24 hours). This radiotracer is used clinically to evaluate dementia, stroke, lack of brain perfusion ("brain death"), cerebral vascular reserve, or risk of stroke (acetazolamide challenge study) and to localize a seizure focus for surgical removal. 0

0

/o\ \

0

H20— CH2

so" H3C

'so'

\2 CH3

Technetium Bicisate

Technetium Dtsofenin

Technetium

Disofenin Injection.

A sictik

colorless solution of disofenin is complexed with Tc-99o pertechnetate after reduction with a stannous salt. The pit cise structure of the technetium complex is unknown at hi' time. Costello et al.7 specify, however, that an analoguesl this Tc-99m—lidofenin complex provides a single technetium (Ill) distorted octahedral (1:2) complex with a coorti nation number of 6. A newer biliary imaging agent is Te 99m mebrofenin, which is more lipophilic because it Ia. bromine on the benzene ring. In the presence of high scan bilirubin levels, there is less renal excretion because of higher lipid solubility. In addition, the product is more which makes it more cost-effective for a centralized pharmacy. The patient receives an intravenous injection of 5 nil.

(185 MBq) of Tc-99m disofenin. which is taken up by it' hepatocytes in the liver by active anionic transport. list the radiopharmaceutical is excreted in bile, via the bins canaliculus, into the bile ducts, with accumulation in I gallbladder and finally excretion via the common bile dal into the small bowel. The normal patient exhibits mulation of the radiopharmaceutical in the livcrandthegtl bladder and small bowel can be visualized within I hours after injection. An example is seen in Figure 13-5 The primary clinical indication for this study is acute cholecystitis. In acute cholecystitis, there is of the cystic duct leading to the gallbladder. The galiblailL"

Technetium (Tc-99m) Depreotide Injection. Technetium depreotide injection is a new radiolabeled synthetic

is not visualized because the radiotracer cannot enter Some other clinical conditions that can be diagnosed bylt:

Chapter 13 • Agents for Diacnoojc Imaging

i

0

images are common bile duct obstruction. biliary teak surgery. biliary atresia. and a choledochal cyst.

from

0 Exametazime Injection.

A sterkcolorless solution ol exametasime is complexed with Tc$Jm perlechnelate after reduction with a stan000s salt. The pacise structure of the technetium complex is unknown at time. Jurisson et al.° speciry. however, that analogues il this complex Tc-99m propylene amine oxime provide a (VI square pyramidal complex with a coordinaion number of 5. This radiopharmuceutical is lipid-soluble Technetium

and. therefore, crosses the blood—brain harrier and is trapped

the brain. The possible mechanisms proposed for lo-

ulization include binding to glutathione. change in ionic tale, and chctnical degradation. The patient receives an ininjection of 20 mCi (740 MBq) of Tc-99m examet-

uime in a controlled environmental state. The patient is spine, with covered eyes (20 minutes). in a quiet room and sfrh indirect lighting prior to injection. The radiopharmaceuis irreversibly bound to the brain after 10 minutes. Some

indications for this study are localization of seizure

ki, evaluation ofdcinentia. identilication of drug abuse—inbrain defects (i.e.. cocaine), and evaluation of strokc. The normal study is represented by a homogeneous and sym-

zetric distribution of radioactivity throughout the brain. Cer-

activity is usually greater than activity in the rest of frebraiit. This is the agent of choice to determine brain death

.n patients on life support systems. The major use of this at this time is the radiolubeling of nulologous leukocytes as an adjunct in the localization of rim-abdominal infection and inllammaloiy bowel disease.

Medronate Injection. A sterile, solution containing sodium medronate (methylene Jiphosphonate) and a stannous salt is complcxed with TcThu pertechnelate. A structure proposed by Libson et the technetium ntedronate complex is shown below. De Litsy et alY' specify. however, that Tc-99m bone imaging Technetium

OH

0—P

fr

Technetium Oxidronate

Technetium Mertiatide Injection. The technetiunt mertiatidc complex is a sterile, colorless solution of meiliacide complexed with Tc-99m pertechnetate after reduction with a stannous salt. The precise structure is shown below. This radiopharniaceutical is the agent of choice to provide

information about relative function of the kidneys and urine outflow because ii has a higher extraction efficiency than Tc-99m pentetate. Indications include renal artery stenosis in nonperlused kidneys, renal transplant assessment, and outflow obstruction. The patient receives a bolus intravenous injection of 10 mCi (370 MBq) of Tc-99m mertiatide. and dynamic images are obtained every 3 to 5 seconds to study blood flow to the kidneys. Sequential static images are then obtained for 20 to 30 minutes to evaluate renal cortical up. take, excretion, and tubular clearance. Delayed images may he required to evaluate patients with obstruction or renal failure. Normally, there is prompt symmetric bilateral perfusion, good cortical accumulation bilaterally with visualization of the collecting systems by 3 to 5 minutes postinjection, and rapid excretion into the bladder, with no delay to indicate

partial or complete obstruction. An older renal imaging agent, Tc-99m gluceptate (a Tc-99m hydroxy acid complex; see below for the ligand), is now used as a transchelation agent for radiolabeling monoclonal antibodies.

are mixtures of many components (polymers and that can be separated by high-performance anion chromatography. The clinical use olthis agent is for investigation of skeletal such as metastatic disease to the hones. osteomyeI;is. Paget's disease, fractures, primary hone tumors. avasnlar necrosis. metabolic bone disease, and loose or infected hp prostheses. Stress fractures can be diagnosed by bone

ruging when x-rays are completely normal. Bone radiois one of the most commonly performed nuclear diagnostic procedures because the whole-body sur-

Technetium Mertiatide

allows evaluation of the entire skeleton, which cannot us cost-ellectively by any other imaging modality. The patient receives an intravenous injection of 15 to 20 4555 to 740 MBq) of Tc-99m medronate. which localin bone according to the degree of metabolic activity. niedronate is absorbed onto hydroxyapatite crystals of the ol new bone formation with about 50 to dtse distributed throughout the skeleton within 3 hours: the rest is excreted by the kidneys.

A tewcr bone-imaging agent. Tc-99m oxidronate (a bygroup on the carbon of medronate) has a higher bindaffinity for hydroxyapatile crystals in bone: however. criteria indicate no advantage to use of this agent.

465

Technetium Gluceptale

466

Whoa,,

and

TeribooA of Organie Mediehuil and ('lu,n,,at-,'uueal Clw,niorv

Technetium Pentetate Injection. A sterile. colorless or slightly yellow solution of sodium pentetate or calcium trisodium pentetate is complexed with Tc-99m pertechnetace after reduction with a stannous salt. The precise

successful surgical splenic transplants by using heat-damS aged RBCs.

structure of Tc-99m pcntetate is unknown: howevcr. .lurisson et alP suggested the possible structure below. The primary clinical use of this agent is for renal studies and glomerulur

colorless solution of .sestamibi is synthesized by reaction with Tc-99m pertechnetute after reduction with a stannour salt. The precise structure of the technetium complex is Tc99m (MIBI)5 . where MlBl is 2-methoxyisobutyl This was the first Tc-99m—labeled agent introduced to replace thallous (201Th chloride for myocardial perfusion imaging. The shorter half-life of Tc-99m (6 hours) than of 11-

filtration rate (GFR). hut it is occasionally used for brain death and brain tumor localization. The patient receives an intravenous injection of 3 to 20 mCi (Ill to 740 MBq). and the kidneys are imaged for 20 to 30 minutes. The GFR is calculated by a quantitative method using a combination of imaging and counting the radioactivity in serum and urine samples. Normal extraction efficiency is 20% (80 to 140 mlJmin). +

Technetium

"Tc,) Sestamibi Injection.

A sterile.

201 (73 hours) allows administration of a larger dose, which

provides better image quality. Another major difference from Tl-201 is that Tc-99m sestamibj exhibits little "redistribution." or movement out of the myocardium back into the bloodstream. This cytosol binding of sestamihi more flexibility in the imaging time, although it also necescitates separate sestamibi injections at stress and at resting. which increases the expense of this method. The other radiotracers currently used to evaluate dial perfusion include Tl-20l and Tc-99m tetrofosinin.

COOH

cardial perfusion studies usually compare "stress" or creased blood flow images with resting images. The slrcs% can be brought about by physical means (treadmill. bicyclci

or by pharmacological vasodilation (with dipyridamote. COOH

HOOC

Technetium (V) Pentetate

Technetium Red Blood Cells (Autologous,). A sterile reaction vial containing stannous citrate (Ultratag RBC kit) is used to radiolabel a patient's red blood cells (RBCs) with Tc-99m pertcchnetate. Briefly, the patient's blood (Ito 3 mL) is drawn with acid citrate dextrose (ACD) or heparin (100 units) used as an anticoagulant. The blood is labeled with the patient's name and hospital number and added to the sterile reaction vial. After mixing and incubation for 5 minutes. sodium hypochlorite (6 mg) is added to the vial to oxidize excess stannous ions (Sn + 4), A citrate buffer is added to adjust the pH to about 7.4. Then. 30 mCi (1.110 MBq) of Tc-99m pertechnetate is added to the blood in the vial and mixed and incubated for 20 minutes. Without further preparation, the patient receives an intravenous injection of 25 mCi (925 MBq) of his or her own radiolaheled red blood cells. Three different studies can be perthrmed after injection of the Tc-RBC. First, the radionuclide ventriculogram study for evaluation of cardiac function can be done as with Te99m albumin (discussed above). Use of Tc-RBCs is considered the superior technique because the Tc-99m red blood cells remain in the circulating blood volume, whereas the Tc-99m albumin leaks into the extracellular spaces. This leakage increases the background radioactivity around the heart and contributes to degradation of the blood pool image. Second. the Tc-RBCs are used Ibr noninvasive localization of the preoperative site of active gastrointestinal (GI) bleeding. Patients are injected with their own Tc-RBCs. which remain within the circulating blood long enough to extravasate and accumulate within the bowel lumen at the site of bleeding. The final use of Tc-RHCs is to evaluate the spleen after trauma or to confirm an accessory spleen or to study

adenosine. or dobutamine). Myocardium with significanri) narrowed arterial supply may appear to have normal bkx+J flow at rest hut, during increased blood flow during exercice, demonstrate abnormal blood flow relative to areas with nor inal arteries. There are a variety of protocols for the rest imaging sessions, even one that combines Tl-20l and Tc-99m—sestamibi (stress). Additional indications the use of the Tc-99m—sestamibi complex now include itt preoperative localization of parathyroid adenoma and itt early diagnosis of breast cancer. CH2C(CH3)20CH3 N

H3CO(H3C)2CCH2

C\J

H3CO(H3C)2CCH'

,CH2C(CH3)20CH3

'C

N

I,,

N

CH2C(CH3)20CH3

—

Technetium Sestamibi

Technetium

Sodium Pertechnetate.

Tech':

tium sodium pcrnechncuate is a sterile, colorless solution ar taming sodium pertechnetate in normal

(0.9% NaCl. obtained by elution of the sterile Mo—9'+l'h 99m generator. The pertechnelate ion whiehh an ionic radius and charge similar to those of the (l). is concentrated in the thyroid, salivary glands. stomach, and choroid plexus in the brain. It cart Ice ed directly from the Mo—9911'c-99tn generator to image it! thyroid. Meckel'sdiverniculuin (stomach tissue tine), and salivary glands for tumors and to detect

Chapter 13 • Agen:.c for Diagnostic imaging that disrupt the blood—brain barrier (i.e.. tumors, abscesses. Unlike the iodide ion, the pertechnetate ion is not

to thyroid hormone but only trapped. Thyroid nodules can appear nonfunctional, with little or no radiotracer present. These nonfunctional nodules have about a 20% probability of being cancerous and generally require biopsy. The patient receives an intravenous injection of 5 to 10 mCi (ISS to 370 MBq) of Tc-99m pertechnetate. and images are obtained of the thyroid 0 to 20 minutes after injection. The usual dose for the other imaging procedures is the same for Meekel's diverticulum and salivary glands. and 20 mCi (740 MBq) is used for brain tumor imaging.

SuccimerInjection. Tedtnetium A sterile. colorlms solution of succimer (2.3-dimercaptosuccinic acid) is complexed with Tc-99rn pertechnetate after reduction with stannous salt at acid pH. The precise structure of Tc-99m 1111 succimer is unknown: however. Moretti et al.'' sugthe possible structure below. Tc-99m succimer is very useful (or demonstrating the functioning renal parenchyma. kcausc about 409c of the dose is bound to the renal cortex I hour after injection. The patient is injected with 5 mCi (11(5 MB4) of Tc-99m succimer. and multiple images are taken 2 to 4 hours later. This study can be useful for evaluatisp renal trauma, renal masses (e.g.. tumors. cysts). and renal Tc-99m succinser is the diagnostic agent of choice a children who have chronic urinary tract infections causing renal scarring, lithe pH is adjusted to 8.0 to 8.5. a technetium

V-succimer complex is formed, which is useful for imaging tumors.'2 Blower et al.15 have proposed the following nurture fur Tc-99m (V) succinser.

467

des. The particle size of the colloid is 0.1 to 3 After intravenous injection of 5 to 10 mCi (185 to 370 MBq) of Tc-99m sulfur colloid, the radiopharmaceutical is rapidly cleared from the blood by the RE cells of the liver, spleen. and bone marrow. Uptake of the Tc-99m—sulfur colloid depends on the relative blood perhision rate and the functional capacity of RE cells. In the normal patient. 85% of the radio-

colloid is phagocytized by Kupffer cells in the liver, 7.5% by the spleen, and the remainder by the bone marrow, lungs. and kidneys. Bone marrow imaging studies are performed I hour after injection of 10 mCi (370 MBq) of Tc-99rn—sulfur colloid. Normal bone marrow will take up the radiocolloid. but diseased bone marrow appears as "cold" defects in pa-

tients with tumor deposits in the marrow. Tc-99m—sulfur colloid is used usa secondary agent in liver and spleen imag.

ins if Tc.99un—albumin colloid is not available. It is used as the primary agent, however. for GI studies such as gastroesophageal retlux (GER) and gastric emptying of solid food. Gastroesophageal reflux imaging is performed after having

the patient swallow acidified orange juice mixed with Tc99m—sulfur colloid. Normal patients have no GER. This study reportedly has 90% sensitivity in detecting GER. Gastric emptying imaging is performed after the patient swallows solid food (i.e.. scrambled eggs or pancakes) radiola-

beled with Tc-99m sulfur colloid. In general, the normal gastric emptying half-time is less than 90 minutes for solid food.

Technetium Tetrofosmin Injection. A sterile. colorless solution of tetrofosmin is complexed with Tc-99m pertechnetate after reduction with a slannous salt. The precise structure of the technetium complex is shown below)' The formulation contains gluconate to Ibrm a weak technetium (V) chelate to keep the technetium in the (V) oxidation stale for tranuchelatiun to form the technetium (V)—tetrofosmm complex. Technetium (V)—tetrofosmin is another cationic Tc-99ns complex that thallous (201T1) chloride accumulates in viable myocardium. Myocardial uptake of this agent

in humans is about 1.2% 5 minutes afier intravenous injection and decreases to 1.0% at 2 hours. This agent was less specific for detecting ischcmia (66%) than Tl-20l chloride (77%) in a small study (252 patients). ft appears. however. to have rapid clearance through nontarget organs (liver) and thus fewer high-background imaging problems.

0

[ H,c

I1.C I

Technetium (V) Succimer

Sulfur Colloid Injection. Technccolloid injection is a sterile, opalescent colloidal

HC

\\

/

CH.

0 ic

Technetium

of sulfur, a unit of structure built up from poly-

CH.

senic molecules and ions (micellcs) radiolabeled with Tc49m pertechnetate formed by heating in dilute hydrochloric

The radiocolloid should be stahilii.ed with gelatin A inhibit clumping of the negatively charged colloidal parti-

Technetium Tetrofosmin

OC.H,

468

Wilson and Gisvolds Textbook of Organic Medicinal we! Pharmaceutical Chen,i.cgrv

FLUORINE RADIOCHEMISTRY The useful radioisotope of fluorine for organ imaging is fluo-

rine-l8. Fluorine-IS is produced in a cyclotron by the '50(pn)'8F nuclear reaction. Fluorine-IS = 109 minutes) decays by electron capture and positron emission to oxygen-IS with v-ray emissions of 511 keV (194%). Fluorine- IS can be attached to a number of physiologically active

molecules and, with the great strength of the C—F bond. appears to be a very useful label for radiopharmaceuticals.'5 Radiotracer production involves relatively complicated synthetic pathways.. however, and the preparation of high-specific-activity compounds presents many problems. The short

half-life of fluorine-IS makes it necessary to complete the synthetic and purification procedure within 3 hours. Consequently. a separate chemistry system (black box type) is needed for each compound. The chemistry of fluorine is complicated, but some compounds can be fluorinated by '8F exchange reactions and direct fluorination with elemen-

tal fluorine (°'F2): also, compounds with an aromatic ring may he fluorinated by several synthetic reactions. For exam-

ple, partially fluorinated heteroaromatics are readily obtained by the conversion of an amino group on the aromatic ring to fluoride, with use of the BaIz-Schiemman and several related reactions.

Fluorine The r8F)-2-Fluoro-2-Deoxy-o-Glucose. only F-IS radiopharmaccutical presently available is fiuorifle ("5F)-2-lluoro-2-deoxy-o-glucose (F- 18 FDG). The pre-

cise stnacture of F-IS FDG is shown below. It is the only PET agent approved by the FDA. Hamacher et al.'6 introduced the current method of synthesis of F- 18 FDG by nucleophilic fluorination. Use of this radiotracer for diagnostic imaging in oncology has increased dramatically in the last several years. It is used also as a myocardial viability agent and in evaluation of seizure disorders)1 The high glycolytic rate of many neoplasms compared with that of the surrounding tissues facilitates tumor imaging with this glucose analogue. Because of the widespread anatomical distribution of metastases. a whole-body imaging technique using a tumorspecific radiophannaceutical is very useful for tumor detection and mapping to evaluate the extent and relative metabolic activity of the disease.

capture to stable zinc-67 with principal v-ray emissions of 93 keV (38%), 185 keV (24%), and 300 keV (16%). The radiotracer is isolated by dissolution of the target in hydrochloric acid followed by isopropyl ether extraction of he gallium-67 from the zinc and other impurities. The gallium. 67 is back-extracted from the isopropyl ether ink, 0.2 N hydrochloric acid, evaporated to dryness, and dissolved a sterile, pyrogen-free 0.05 M hydrochloric acid. Gallium is an amphoteric element that acts as a metal at low p1-1 hut forms insoluble hydroxides when the pH is raised above 2.0 in the absence of chelating agents. At high pH. gallium hydroxide acts as a nonmetal and dissolves in ammonia tu form gallates. Gallium forms compounds of oxidation

+ I - + 2. and + 3: howcvcr. only the Ga

state is stable

in aqueous solutions.

Gallium

Citrate. The gallium (111)—citrate complex is formed by adding the required amount of sodium citrate (0.15 M) to gallium (Ill) chloride and adjusting the pH to 4.5 to 8.0 with sodium hydroxide. The proposed stOicture of gallium (61Ga) citrate is shown below.6 The paliem receives an intravenous injection of 5 to 10 mCi (185 to 370 MBq) of gallium (67Ga) citrate, and whole-body images are then obtained 24, 48, and 72 hours after injection. Gallium

localizes at sites of inflammation or infection as well aa variety of tumors. his used in clinical practice in the staging and evaluation of recurrence of lymphomas. Gallium localizes normally in the liver and spleen, bone, nasopharyro. lacrimal glands, and breast tissue. There is also some seaslion in the bowel; consequently, the patient may require a laxative and/or enemas to evacuate this radioactivity prior

to the 48-hour image. As more specific radiotracers been developed, the nonspecific normal localization of gal-

lium radioactivity has limited its clinical use.

HO Gallium Citrate

HO -

IODINE RADIOCHEMISTRY Fluorodeoxyglucose

GALUUM RADIOCHEMISTRY

The useful radioisotopes of iodine for organ imaging a: iodine-l31 and iodine-123 because of their desirable p1ns cal characteristics. Iodine- 131 is obtained from a reacrnrfr production of tellurium- 131. It is formed by the nuclear tion 235U(n,fission)'3tTc or 130Te(n,gamma)'"Te. Then:

lurium-l3l (1102 = 25 minutes) decays by

The only radioisotope of gallium that is presently used is

sion to iodine- 131. Iodine- 131 (11,2 = 8.04 days) translniii

gallium-67. which is produced in a cyclotron by proton bomnuclear bardment of a zinc metal target by a = 78.2 hours) decays by electron reaction. Gallium-67

by fi decay to stable xenon- 13 I. with five significant emissions of 80 to 723 key. The major v-ray of 364 ke\ (82%) provides good tissue penetration for organ

Chapter 13 • Agencc for Diagno.clk hnag!ng

469

Undesirable properties of iodine-13l are the high radiation Jose from the f3 particles, the long half-life, and the poor Iodine-I23 rage produced by the high-energy = 13.3 hours) decays by electron capture to tellurium-l23.

in the regional lymph nodes, bone, bone marrow, and soft tissues. After an initial report by Kimmig et al.2° of 1311,

principal y-ray emission of 159 keV (83%), which

makes it the ideal radioisotope of iodine for organ imaging of increased detection efficiency and reduced radia-

is so tisstte specific that it can establish the diagnosis of neurobla,stoma in a child with a tumor of unknown origin. The patient is treated with Lugol's solution (up to 40 mgI

to the patient. lodine-l23 is produced in a cyclotron

day) 24 hours before and 4 to 7 days after administration of

tombarding an antimony metal target with a particles according to the reaction or an iodine target nuclear reacsith high-energy protons by the den. The xenon- 123 decays by electron capture to iodineIt is. however, relatively expensive to produce and curvntl,v has limited availability for radiolabeling compounds. ojine is in group VIIB with the other halogens (fluorine. bromine, and astatine), in aqueous solution, corn-

the radiopharmaceutical, to block thyroid uptake of free 31I. The 131l-MIBG is administered by slow intravenous injection 0.3 to 0.5 mCi (II to 18.5 MBq). and patients are

with a

çounds of iodine are known with at least five different oxidanon states: however, in nuclear medicine, the — I and + I snidation states are the most significant. The — I oxidation

'tue represented as sodium iodide (NaI) is important for

MIBG uptake in neuroblastoma. successful use of this tracer was described by others. The increased uptake of

imaged 24, 48. and 72 hours later. Occasionally, the patient receives a renal imaging agent for better localization of the adrenal tumor.

CH2— NH — C=NH

NH3 • ½S042 1311

tobenguane Sutfate

thyroid studies and, when obtained in a reductant-free solu-

sm (no sodium thiosulfate). is the starting compound for be radiolabeling of most iodinated radiopharmuccuticals. 11w common methods for introducing radioiodine into orasic compounds are isotope exchange reactions. electrosubstitution of hydrogen in activated aromatic sysaims. nucleophilic substitution, and addition to double The replacement of aromatic hydrogen in activated systems is used for protein labeling, and clectroiodine (I') can be generated by a variety of oxidizing acnts. including (a) chloraniine-T (N-chloro-p-toluene sulcosmidel sodium. (b) enzyme oxidation of 1 (lactoperoxilad, and (c) iodogcn I .3.4.6-tetrachlora-3a-6a-diphenylThe actual iodinating molecule depends on the inidizing agent but is probably HOl or H01

Sodium Iodine ('RI) Capsules.

The major indications for thyroid imaging with sodium iodide are for evaluation of thyroid morphology, for ectopic thyroid tissue (e.g.. lingual or mediastinal), and for subslernal thyroid tissue. When thyroid nodules are being evaluated for possible thyroid cancer. 1231 has an advantage over Tc-99m pertechnetate

scans, although 1-123 is more expensive. This is because thyroid cancer cells sometimes retain the ability to trap, hut not further process, iodine to thyroid hormone. Unlike iodine. Tc-99rn pertechnetate is only trapped by the thyroid and in a nodule may give the false impression that a nodule is not cancerous. The patient fasts before receiving the oral dose of 0.4 mCi (IS MBq) of sodium iodine 0231). Images are obtained of the thyroid and surrounding area 4 to 6 hours after ingestion.

(obenguane Sulfate r311.) Injection a-131—Metaiodolobenguane sulfate is rabeflzylguanidine Sulfated.

by a Cu -catalyzed isotopic nucleophilic exlarge reaction. It is a radioiodinated arylalkylguanidine and similar to the antihypertensive drug guanethidine and to norepincphrinc. The proposed structure ciobenguane

sulfate is shown below. Iodine-123 is

used to radiolabel this tracer and may have more favora:Ic imaging properties. Functional tumors of the adrenal meMb (pheochromocytomas) and tumors of neuroendocrinc mis (neuroblastoma) can be localized on 1-131 ,neta-iodo-

enoylguanidine ('31l-MIBG) images, as abnormal tissue at takes up the radiopharmaceutical and exhibits increased tthity on the image)9 Drug intervention studies in animals. sing reserpine. have demonstrated that the 311-MIBG en-

adrencrgic neurons and chromaffin cells by an active :ansport mechanism of catecholamine uptake into adrener3C granules.

is a malignant tumor of the sympathetic mous system, which occurs most often in children. The anorisof neural crest origin and consists of cells that form nervous system, called svrnpashogonia, that to the adrenal medulla and many other parts of the Metastases may be found in the liver (stage IV) and

Sodium Iodine P37l) Oral (Solution or Capsule).

The

thyroid cancer patient receives an oral dose of 5 to 10 mCi (185 to 370 MBq) of sodium iodide (1311). which localizes

in residual thyroid tissue after "total" thyroidectomy and functioning thyroid metastasis from thyroid carcinoma. Images of the whole body are obtained 48 to 72 hours later. These mctastatic radioiodide surveys are used to detect regional or distant metasrases for large-dose 150 mCi (5.550 MBq) inpatient therapy for thyroid carcinoma. Any thyroid hormone medication should be discontinued for 2 weeks (Ti) or 4 weeks (T4). In addition, the patient should have blood

drawn for a thyroid-stimulating hormone (TSH) test to ensure that TSH is elevated before administration of the therapy dose, to permit maximum stimulation of thyroid tissue. The patient should fast before receiving tbe oral dose of radiotracer.

INDIUM RADIOCHEMISTRY The most useful radioisotope of indium is indium-Ill, which is produced in a cyclotron by proton bombardment of a cadmium metal target by a °2Cd(p.2n)' nuclear reaction.

470

Wi/eon and GLnold 's Textbook of Organic Medicinal and Pharmaceutical O,e,nistrv

Indium-Ill

= 67.4 hours) decays by electron capture to stable cadmium-Ill with principal y-ray emissions of 172 key (91%) and 247 keV (94%). The radiotracer is isolated

(MW —55.000) and two light chains (MW —20.0(X)) of gly. coproteins. held together by disulfide bonds. Many tumors

by dissolution in hydrochloric acid to form "In-chloride

tion with radiolabcled antibodies. Antibodies are produced by B lymphocytes and plasma cells sensitized to an antigen. Hybridoma technology permits the manufacture of large quantities of antibody directed against specific antigens. Diagnostic antibodies are of two types: polyclonal and mono-

and separated from cadmium and other impurities by several dissolution and extraction steps. The last extraction is done with isopropyl ether, evaporating to dryness, and dissolving in sterile. pyrogen-free 0.05 M hydrochloric acid. In aqueous solution, lower valence states of indium have been described. but they are unstable and are rapidly oxidized to the trivalent state. In acid solution, indium salts are stable at low pH but

arc hydrolyzed (above pH 3.5) to form a precipitate of indium hydroxide or tnoxide. Indium will remain in solution above pH 35. however, if it is coniptexed with a weak chelating agent such as sodium citrate and stronger chelating agents such as 8-hydroxy quinoline (oxine) or diethyleneu'iaminepemaacetic acid (DTPA). Monoclonal antibodies or peptides are radiolabeled by indium by using compounds called hiji,nctiunal chelating agents. Bifunctional chelating agents are molecules that can both hind metal ions and be attached to other molecules: one example is the cyclic anhy-

dride of DTPA.

express antigenic markers on their surfaces that permit detec-

clonal. Each chain has a variable region for antigenic binding

and a constant region for complement fixation. Polyclonal antibodies include numerous antibody species of varying at• finity for the antigen-binding surfaces. Monoclonal antibod. ies are generated from a clone of a single antibody-producing

cell and have uniform affinity for their antigenic demenninant2' Monoclonal antibodies are produced by immuni/ing a mouse with purified material from the surface of the human

tumor cell. (See Chapter 7 for additional information.) ha antigen used in Oncoscint CRJOV is a tumor-associated glycoprotein-72 (TAG-72). a high-molecular-weight glycopro. tein expressed by colorectal and ovarian The

radiolaheling of Oncoscint CRJOV monoclonal a

Indium Radiopharmaceuticals Indium ("'In) Chloride Injection.

Indium (111) chlo-

ride is a sterile, colorless solution that is radiolabeled with indium-I II in a hydrochloric acid solution ((1,05 M) and has a pH of 1.5. It is primarily used to radiolabel other compounds for use in cistemography and white blood cell labeling studies and is particularly recommended for radiolabeling nionoclonal antibodies for metastatic cancer imaging. If this agent is injected intravenously for clinical use, the patient's blood must be drawn into the syringe containing the radiopharmaceutical to buffer the agent to a higher pH to eliminate the burning sensation on injection. When the acidic

compound is mixed with blood, the indium-Ill chloride

site-specific method using

a bifunctional chelate. Briefly, carbohydrate moieties on thc monoclonal antibody (F-constant region) are oxidi,cd esith periodate. and the aldehyde groups on the antibody are aacted with a-amino groups of glycyl-Iyrosyl-lysine-N-dielh.

ylene triarninepentaacctic acid. The Schiff's base (imine) is stabilized by reduction with sodium cyanoboruh).

dride. In-Ill is chelated to a DTPA-curbohydrate attached to the constant region of the monoclonal anlibesi). The specificity of radiolaheled antibody imaging (or tumon exceeds that of gallium (°7Ga) citrate studies. Sites of non specific uptake have been reported, however, such as recenT surgical wounds, arm infianied colon, bone fracture, and nor-

mal colostomy stoma. A new nlcIlRxl of labeling with Ic99rn has recently been approved by the FI)A.

hinds quickly to transferrin. the iron-binding protein in the plasma. The localization of the indium (Ill) chloride in bone marrow is probably explained by its ability to behave metabolically like iron and yet not be incorporated into heinoglobin in the RBCs in the hone marrow. The localization of the radiotracer in tumors and abscesses is probably due to increased blood flow and capillary permeability in the area of tissue damage. Transferrin receptors have been suggested

as a means of localization but not proved at this time.

Indium

capromab Pendetide. Indium capromab pendetide is a new radiotracer for staging patients with

Fc Region

newly diagnosed prostate cancer and for those with suspected reoccurrence but a negative localization with a standard evaluation.

Indium ("'In) Oncoscint The simplified structure of indium (° 'In) satumomabpcndetide is shown below. Antibodies are a heterogeneous group of proteins isolated from human and animal serum

and are called i:nmunoglobulins. They are divided into classes on the basis of

in structure and biological

properties and are assigned to major classes called lgG (80%). 1gM (100/c). and IgA. lgD. IgE ( secondary > primary. In part.

Meprobamate is also a centrally acting skcletal muscle relaxant. The agents in this group find use in a number of conditions, such u.s strains and sprains that may produce acute muscle spasm. They have interneuronal blocking prop-

erties at the lcvel of the spinal cord, which are said to be partly responsible for skeletal muscle relaxation.27 Also, the general CNS depressant properties they possess may contribute to. or be mainly responsible for, the skeletal muscle relax-

ant activity. Dihydric compounds and their carhamate (urethane) derivatives, as described above in the discussion of meprobamate. are prominent members of the group.

CH,—CH2—CH5 0

0

H

Carisoprodo!

Chlorphenesin Carbamate.

= —CH(CH,).

Chlorphenesin carbaniate. 3-(p-chlorophenoxy)- I .2-propanediol I -carbamate (Mao-

496

Teeibook

WiLco,, and

of Organic Medicinal and

late). is the p.chloro substituted and I -carbamate derivative of the lead compound in the development of this group of agents, mephenesin. Mephenesin is weakly active and short-lived because 01' facile metabolism of the primary hydroxyl group. Carhamy-

lution of this group increases activity, p-Chlorination increases the lipid/water partition coefficient and seals off the para position from hydroxylation. Metabolism, still fairly rapid, involves glucuronidation of

C'he,ni.czrv

and formate ion. In hydroalcoholic solutions, it forms the hemiacetal with ethanol. Whether or not this compound is the basis for the notorious and potentially lethal effect ol the combination of ethanol and chloral hydrate (the "Mickey

Finn") is controversial. Synergism between two different CNS depressants also could be involved. Additionally. ethanol, by increasing the concentration of NADH. the reduction of chloral to the more active nietabolite trichiw roethanol, and chloral can inhibit the metabolism of alcohol

the secondary hydroxyl group. The biological half-life in

because it inhibits alcohol dehydrogenase. Although it

humans is 3.5 hours.

suggested that chloral hydrate per se may act as a chloral hydrate is very quickly converted to trichloroethanol, which is generally assumed to account for almost all of the

hypnotic effect. It appears to have potent barbiturate-like binding to GABAA receptors. Chiorphenosin Carbamate

Methocarbamol,

USP. Methocarbamol, 3-to-methoxyphenoxy)- I .2-propanediol I -carhamate (Robaxin). is said to be more sustained in effect than mephenesin. Likely

sites for metabolic attack include the secondary hydroxyl group and the two ring positions opposite the ether functions.

The dihydric parent compound, guaifenesin. is used as an

Tridofos Sodium.

Triclolis sodium, 2.2,2,-trichksroethanol dihydrogen phosphate monosodium salt (Triclus). irritating to the 01 mucosa. Its active nictabolite. trichlorwthanol. also has unpleasant 01 effects when given orally Triclofos is the nonirritating sodium salt of the phosphate ester of trichloroethanol and is readily converted to roethanol. Accordingly, triclofos sodium produces CNS fects similar to those of oral chloral hydrate.

expectorant.

CI3C—CH,O—P---O Na' ?F1

0— CH2 — CH — CH2OIR Gualtenesin

P

Triclolos Sodium

H

Paraldehyde, USP. Meihocarbamol R=—C—NH?

Carisoprodol,

N-isopropyl-2USP. Carisoprodol. methyl-2-propyl- I .3-propanediol dicarbamate. 2-methyl-2isopropylcarbamate propyl- I ,3-propanediol carbamate (Soma). is the mono-N-isopropyl—substituted relative of meprobamate. The structure is given in the discussion of meprobamate. It is indicated in acute skeletomuscular conditions characterized by pain, stiffness, and spasm. As can be expected, a major side effect of the drug is drowsiness.

Paraldehyde, 2.4.6-trimethyl-o-tn oxane: paraccialdehyde. is recognizable as the cyclic triton

of acetaldehyde. It is a liquid with a strong char,icteristk odor detectable in the expired air and an unpleasant taste Thcse properties limit its use almost exclusively toan in the treatment of delirium trenlens). It the past, when containers were opened and air admiued

then reclosed and allowed to stand, fatalities occuned cause of oxidation of paraldehyde to glacial acetic acid.

CH ALDEHYDES AND THEIR DERIVATIVES

For chemical reasons that are easily rationalized, few aidehydes are valuable hypnotic drugs. The aldehyde in use, chioral (as the hydrate), is thought to act principally through a metabolite. trichloroethanol. Acetaldehyde is used as the cyclic trimer derivative. paraldehyde, which could also be grouped as an ether.

CH Paraldehyde

ANTIPSYCHOTICS Chioral hydrate. trichioroacetal(Noetec), is an aIdehyde hydrate stable enough to be isolated. The relative stabil-

Chloral Hydrate, USP. dehyde monohydrate,

ity of this gem-diol

largely due to an unfavorable

Antipsychotics are drugs that ameliorate mental that are characteristic of the psychoses. The psychoses difirt

dipole—dipole repulsion between the trichloromethyl carbon and the carbonyl carbon present in the parent carbonyl corn-

from the milder behavioral disorders, such a.s the disorders, in that thinking tends to he illogical. bizane.ani loosely organized. Importantly. patients have difficulty a'

pound.25

derstanding reality and their own conditions. There are oftefl

Chioral hydrate is unstable in alkaline solutions, undergoing the last step of the haloform reaction to yield chloroform

hallucinations (usually auditory) and delusions. In the schizophrenias. in addition to these symptota.

is

Chapter 14 a

called j,osiii,e there are negative symptoms represented by apathy, social withdrawal, and anhedonia. Cognitive delicits may also be observed. Psychoses can be organic and related to a specitie toxic chemical c.g.. delirium produced by central unticholinergic Jgents). an NMDA antagonist e.g.. phencyclidinc). a definite disease process e.g.. dementia) or they can be idio-

pathic. Idiopathic psychoses may be acute or chronic. idiopathic acute psychotic reactions have been reported to follow estremely severe short-term stress. Schizophrenia is a group

of chronic idiopathic psychotic disorders with the overall described above. The term w,t,psyrhonc was slow in gaining acceptance. Now it is widely acknowledged that antipsychotics actually diminish (he underlying thought disorder that is the chief characteristic of the schizophrenia.s. The agents often have effect in agitated psychotic patients: hence, they also have been referred to as major Iran quilizers. Finally. kcause they lessen reactivity to emotional stimuli, with little dfect on consciousness, they are referred to as ne:irolepiics. The most frequent uses of these agents are in manic disor-

ders anti the schizophrenias. In the manic disorders, the agents may block DA at limbic D2 and D3 receptors, reducing euphoria, delusional thinking, and hyperactivity. In the chronic idiopathic psychoses (schizophrenias), both conven(typical) and newer (most are atypical) antipsychotics

to act to benefit positive symptoms by blocking DA and D3 limbic receptors.' The bases of the atypical activity against negLdive symptoms may be seroton,n-25 receptor (5-HT2A) block, block at receptors yet to be A Jetermined. and possibly decreased striatal D2 block.' a

classic competitive antagonism has been demonstrated at D3

D receptors. Also, in recombinantly expressed receptas. inverse agonism has been demonstrated. For this to apply in vivo. a ground state of dopaminergic activity must shown. Some preliminary signs indicate this is likely.' In the schizophrenias. which have an extremely complex multifactored etiology.31 the fundamental lesion aprears to be a defect in the brain's informational gating mechJnism. A slight abnormality in the startle response may be

in infancy. hut the disease does not emerge until in the second decade or in the third decade of life. Basithe gating system has difficulty discriminating between relesaun and irrelevant stimuli. Perception is illogical. Pro;eeding from this, thought and actions become illogical. Although the actual structural or anatonsical lesions are not known. the basic defect appears to involve overactivity of dopaminergic neurons in the mesolimbic system. Some insuggest that this is the cause of most, if not all. the common symptoms of the disease. Negative symp:nns Ie.g.. social withdrawal) may be considered secondary .vnlptoms. Others argue that all or part of the foregoing is reductionist, and that other lesions cause some all 1)1 the symptoms. A

reason for the recent interest in the negative of schizophrenia has been the introduction of as opposed to typical. antipsychotics. Typical anti-

began with the serendipitous discovery of the activity of chlorpromazine. Many compounds nrc sytuthcsi,.ed. usually with chlorprornazine as the model. an) the antipsychotic potential assessed. A clear association

the ability to block DA at mesolimbic D2 receptors

Nrn,;sec Sv.qen, Deprt'ssanrs

497

was established. During the same time, amphetamine-induced psychosis was determined to be caused by ovcractivation of mesolinibic receptors and judged to be the closest

of the various chemically induced model psychoses to the schizophrenias. The conventional typical antipsychotics are characterized by the production of EPS. roughly approximating the symptoms of Parkinson's disease. These are reversible on discontinuing or decreasing the dose of the drug and are associated with blockade of DA at D3 striatal receptors. After sustained high-dose therapy with antipsychotics, a late-appearing EPS. turdive dyskinesia. may occur. The overall symptomatology resembles the symptoms of Huntington's chorea. The condi-

tion is thought to arise from biological compensation (increased D2 activity) for the striatal D2 block of antipsycholic drugs.

Atypical antipsychotics date from the discovery of clozapine, its antipsychotic properties and its much lower production of EPS. Some investigators express concern that typical

antipsychotics. especially by producing EPS. introduce drug-induced effects that are hard to distinguish from negative symptoms. This leads to the view that diminishing EPS can account for perecived decreased negative symptoms. It is. however, reportedly also more active against negative symptoms of schizophrenia. independent of reduced EPS. and has a unique, notably expanded, receptor-blocking profile. Compounds are now under synthesis and being tested at the various CNS receptors at which clozapine acts to determine the role of these receptors in schizophrenia. Also contributing to the development of typical antipsychotics was the introduction of risperidone. It has reduced EPS. has increased activity against negative symptoms, and, in addition to its DA blocking ability, is a 5-HT2,5 antagonist. One view of the drug is that it combines structurally the features of an antidepressant and an antipsychotic. and so the two drug effects are attained. Related to this is tile V1CW that at least some negative symptoms (e.g.. depression. withdrawal) are secondary to the positive symptoms. The view has also been advanced, however, that receptors are involved in part (the negative symptoms) or wholly in schizophrenia. So far, the evidence appears to be that 5-HT2A blocking agents do not relieve positive effects of schizophre-

The view that 5-HT2A overactivity is the source of negative symptoms (pan of the basis psychosis) is not disproved at present. though sonic say it has been weakened.3" One result of the development of atypical antipsychotics has been a renewed interest in models of psychosis other than the amphetamine model. In line with possible dual involvement of 5-UT and DA. the lysergic acid diethylamide model has been cited as better fitting schizophrenias than the amphetamine model. But, this has been disputed. Interest in serotoninergic involvement is still high and involves eluci-

dating the roles of 5-UT,, and 5-HT, receptors. Interest remains in understanding the psychosis produced by several central anticholinergics. Muscarinic (M, and M4) agonists appear to offer the best approach at this tinle.-'5 The role of the M5 receptor awaits synthesis of Ms-specific Phencyclidine-induced psychosis has been proposed as a

superior model for schizophrenia because it presents both positive and negative symptoms.51' It sugges(s that deficits in glutantinergic function occur in schizophrenia. Results of

498

Wilson

and Gissolds Textbook of Organic Medicinal and

agonists of NMDA receptors overall have not been productive because of the excitatory and neurotoxic effects of the agents tested. Identification of susceptible receptor subtypes as targets, using glycine modulation or group II metabotropic receptor agonists to modulate NMDA receptors, has been proposed to circumvent the problems associated with the NMDA agonists. The ionotropic glutamic acid a-amino-3-hydroxy-5methyl-4-isoxazole propionic acid (AMPA) receptors are activated by brain-penetrating ampakines. There are suggestions that these agents exert some antipsychotic actions by increasing glutarninergic activity. The individual antipsychotic compounds are flow considered. The substituted dopamine motif is useful as an organizational device. Atypical antipsychotics are indicated when they occur. Future growth in this area should be interesting.

Phenothlaalnes Many potentially useful phenothiazine derivatives have been synthesized and evaluated pharmacologically. Consequently, the large body of information permits accurate statements about the structural features associated with activity. Many of the features were summarized and interpreted by

Gordon et al.35 The best position for substitution is the 2 position. Activity increases (with some exceptions) as electron-withdrawing ability of the substituent increases. Another possibly important structural feature in the more potent compounds is the presence of an unshared electron pair on an atom or atoms of the 2 substituent. Substitution at the 3

position can improve activity over nonsubstituted compounds but not as significantly as substitution at the 2 position. Substitution at position I has a deleterious effect on antipsychotic activity, as does (to a lesser extent) substitution at the 4 position.

——

/

—N

I

A3

\A- -i

Phenothiazine Antipsychotic Agents—General Structure

The significance of these substituent effects could be that the hydrogen atom of the protonated amino group of the side

chain H bonds with an electron pair of an atom of the 2 substituent to develop a DA-like arrangement. Horn and Snyder. from x-ray crystallography, proposed that the chlotine-substituted ring of chlorproniazine base could be superimposed on the aromatic ring of dopamine base with the

sulfur atom aligned with the p-hydmxyl of dopamine and the aliphatie amino groups of the two compounds also aligned.36 The model used here is based on the interpretation of the SARs by Gordon et al.5° and on the Horn and Snyder

but involves the protonated species rather than the free base. The effect of the substituent at the I position might be to interfere with the side chain's ability to bring the protonated amino group into proximity with the 2 substituent. In the Horn and Snyder scheme.36 the sulfur atom at

CIaemistr4

position 5 is in a position analogous to the p-hydroxyl of dopamine. and it was also assigned a receptor-binding func-

tion by Gordon et al.35 A substituent at position 4 might interfere with receptor binding by the sulfur atom. The three-atom chain between position 10 and the amino nitrogen is required. Shortening or lengthening the chain at this position drastically decreases activity. The three-atom chain length may be necessary to bring the protonated amino

nitrogen into proximity with the 2-substituent. As expected, branching with large groups (e.g.. phenyli decreases activity, as does branching with polar groups. Methyl branching on the f3 position has a variable effect on activity. More importantly. the antipsychotic potency of leos (the more active) and dexi'ro isomers differs greatly. This has long been taken to suggest that a precise lit (i.e.. receptor site occupancy) is involved in the action of these Decreases in size from a dimethylamino group (e.g., going to a monomethylamino) greatly decrease activity, as do cf fectivc size increases, such as the one that occurs with N.N diethylamino. Once the fundamental requirement of an effec. live size of about that equivalent to a dimethylamino is mainS tamed, as in fusing N.N-dicthyl substituents to generate a pyrrolidino group, activity can be enhanced with increasing chain length. as in N2-substituted piperizino compounds. The critical size of groups on the amino atom suggests

the importance of the amino group (here protonated) for receptor attachment. The effect of the added chain length. once the critical size requirement is met, could be increased affinity. It appears to have been reasonably proved that thc

protonated species of the phenotlsiazines can bind to DA receptors.37

Metabolism of the phenothiazines is complex in detail, but simple overall. A major route is hydroxylation of the tricyclic system. The usual pattern, for which there are good chemical reasons, is hydroxylation pars: to the lO-nitrogcn atom of the ring other than the ring bearing the electron. attracting substituent at the 2 position. Thus, the major metabolite is frequently the 7-hydroxy compound. This corn pound is further metabolized by conjugation with glucuronic acid, and the conjugate is excreted. Detailed reviews of the metabolites of phenothiazines (as well as SARs and pharwacokinetic factors) are available.38 PRODUCTS

The structures of the phenothiazine derivatives descñbol below are given in Table 14-3.

Promazine. Promazine, I0-(3-(dimethylamino) propyl. (phenothiazine monohydrochloride (Sparine), was intro duced into antipsychotic therapy after its 2-chloro-subste tutcd relative. The 2H substituent cis-a-vis the 20 substituent gives a milligram potency decrease as an antipsichotic, as encompassed in Gordon's rule. Tendency to EPS is also lessened, which may be significant, especially if it ci

decreased less than antipsychotic potency.

Chiorpromazine Hydrochloride. USP.

Chlorprorna-

zinc hydrochloride. 2-chioro- I 0-[3-(dimethylamino)pro. pyliphenothiazinc monohydrochloride (Thorazine), was the first phenothiazine compound introduced into therapy. II ci

Chapter 14 • ceniral Neniws

Depressants

System

499

TABLE 14-3 Phenothiazine Derivatives

Generic Name Proprietaty Name

R3

R14,

Propyl Dlatkyiamino Side Chain Proma3ino hydrochloride. USP Spanne

—(CH2)3N(CH3)2• HCI

H

—(CH2)3N(CH3)2 HCI

Ci

—(CH2)3N(CH3)2' HCI

CF3

Thioridazine hydrochioride.USP Mellani

—(CH2)2_(') HCI

SCH3

Mesoridazine besylale.USP

._.(CH2)2_C)

Chiorpromuane

USP

Tho,azirme

Triflupromacine hydrochiocide.USP Vespnn

Akyl Piperidyl Side Chain

Sero,1,1

. C6H5SO3H

SCH3

CH3

Propyl

o T

I

Side Chain

Prochiorperazine maleale,USP Compazine

i'"

—(CH2)3—NN—CH3 2C4H404

Triliuoperezine hydrochlormde. USP

2HCI

I'

Ste/azmne

Perphenazrne,USP

—ICH2)3NNCH2CH7—OI-t

Fluprienazine hydrochloride, USP Permitil. Piolixia

—(CH2)3—N

cliii useful as an antipsychotic. Other uses are in nausea vomiting and hiccough. It is the reference compound in comparisons, that is. the compound to which others compared. The drug has significant sedative and hypoproperties, possibly reflecting central and peripheral m1-noradrenergic blocking activity, respectively. Effects of xnpheral anticholinergic activity are common. As with the cher Ithenoihiazines, the effects of other CNS-deprnssant jugs. such as sedatives and anesthetics, can be potentiated.

Triflupromazine Hydrochloride. USP. Trifluproniawe hydrochloride, lO-[3-(dimethylamino)propylj-2-(triflu'mmeihyl)phenothiuzine monohydrochioride (Vesprin). has

r\

N—CH2—CH2--OH 2HCI

Cl

CF3

CI

CF3

a

an

antipsychotic. EPS

are higher. The 2-CF3 versus the 2-Cl is associated with these changes. Overall, the drug has uses analogous to those

of ehiorpromazine.

Thioridazine Hydrochloride, USP.

Thioridazine hy-

drochloride, lO-[2-( I -methyl-2-piperidyl)ethyll-2-( methylthio)phenothiazine monohydrochloride (Mellaril), is a member of the piperidine subgroup of the phenothiazines. The

drug has a relatively low tendency to produce EPS. The drug has high anticholinergic activity, and this activity in the strialum. counterbalancing a striatal DA block. may be responsible for the low EPS. it also has been suggested that there may be increased DA receptor selectivity, which may

500

Wily,,: and (li.s:'old's

of

Methr,nal and Pharn,areu:ieal Ciwmiorv

be responsible. The drug has sedative and hypotensive activ-

ity in common with chlorproinaiine and less antiemetic activity. At high doses. pigmentary retinopathy has been observed. A metabolite of the drug is mesoridazine (discussed next).

Mesoridazine besylate. Mesoridazine Besylate, USP. 2-mcthyl-2-piperidyl )ethyl I-2-(methylsulilnyl)phcnoI thiazinc monobenzencsul Innate (Serentil). shares many properties with thioridazine. No pignscntary retinopathy has been reported, however.

logical properties to the corresponding phenothiazines. Thus. thiothixene (Z.N-dimethyl-9-[3-(4-methyl- I -piperaiinyl)propylidenelthioxanthenc-2-sulfonamide (Navane). dis' plays properties similar to those of the piperazine subgroup of the phenothiazines.

Q(XJL II

H—C—CH2—CH2—N

Prothiorperazine Maleate, maleatc.

N—CH3

\—,

Prochlorperazine USP. 2-chloro- IO-(3-(4—methyl- I -piperazinyl)propyll-

phenothiazine maleate (Compazine). is in the piperazine subgroup of' the phenothiazines, characterized by high milligram antipsychotic potency. a high prevalence of EPS. and Prochiorperazine is low sedative and uutonomic more potent on a milligram basis than its alkylamino counterpart. chlorpromazine. Because of the high prevalence of EPS, however, it is used mainly fur its antiemetic effect, not for its antipsychomic effect.

A dibenzoxazepine derivative in use is loxapine succi' nate, 2-chloro- II -(4-methyl-I -piperazinyl)dibenzib. Jill. 4loxazepine succinate (Daxolin). The structural relationship to the phenothiazine antipsychotics is apparent. It is an

live antipsychotic and has side effects similar to those ic ported for the phenothiazines.

Perphenazine, USP. Perphenazine. nothiazine- IO-yl)propyl Ipiperazineethanol; 2-chloro- 10-1314-(2-hydroxycthyl )pipcrazinyl ipropyl Iphenothiai.ine (Tnlafon). is an effective antipsychotic and antiemetic.

Fluphenazine Hydrochloride. USP.

CH2COOH CH2COOH

The member of

the piperazine subgroup with a trilluoromethyl group at the 2-position ni the phenothiazine system and the most potent antipsychotic phenothiazine on a milligram basis is liuphenazine hydrochloride. 4-13-12-(trifluoromethyl)phcnazin- 10yl J propyl I-I -piperazineethanol dihydrochloride. I 013-14-(2-

hydroxycthyl)pipcrazinyll propyll- 2-tmiiluoromethylphcnothiazine dihydrochioride (Perniitil. Prolisini. It is also available as two lipid-soluble esters for depot intramuscular injection, the ei:anthate (heptanoic acid ester) and the decanoale ester. These long-acting preparations have use iii treating psychotic patients who do not take their medication or are subject to frequent relapse.

Loxapine Succinate

The dibenzodiazepine derivative is clozapine tClozacii'. It is not a potent antipsychotic on a milligram basis

the orientation of the N-methyl piperazino group relative the chlorine atom). It is effective against both positive a low to produce EPS. There are legal restrictions on us use cause of a relatively high frequency of agranulocysosis. A: a rule, two other antipsychotics are tried before recourse to therapy with clozapinc.

Ring Analogues of Phenothlazlnes: Thiozanthenes. Dlbenzoxazeplnes, and UlDenzodlazeplnes The ring analogues of phcnothiuzines are structural relatives of the phenothiazine antipsychotics. Most share many clinical properties with the phenothiazines. 'fhe dibenzodiazepinc clozapinc has some important differences, however, no-

Cl

N

\CH3

tably low production of EPS and reduction of negative symptoms. It is an important atypical antipsychotic. Clorapine

Thiothixene, USP.

The thioxanthene system differs

from the phenothiazine system by replacement of the N-H moiety with a carbon atom doubly bonded to the propylidene side chain. With the substituent in the 2 position. Z and E isomers are produced. In accordance with the concept that the presently useful antipsychotics can be superimposed on DA. the Z isomers arc the more active antipsychotic isomers. The compounds of the group arc very similar in pharmaco-

—- —r--—--—--——

The fluorobutyrophenones belong to a much-studied pin;

of compounds, many of which possess high a few of these are used in the United Suir which can be misleading about the importance of the pin' and its evolved relatives. The structural requirements hi

Chapter 14 • C'en,rul

antipsychotic activity in the group are well worked out. General features are expressed in the following structure. AR

Optimal activity is seen when AR1 is an aromatic system.

Ap.fluorn substituent aids activity. When X = C = 0. optima] activity is seen, although other groups, C(H)OH and

OU)aiyl, also give good activity. When n = 3. activity is tsptimal; longer or shorter chains decrease activity. The aliphatic amino nitrogen is required, and highest activity is

is incorporated into a cyclic form. AR2 is an jnnnatic ring aiid is needed, It should be attached directly to the 4 position or (occasionally) separated from it by one Intervening atom. The Y group can vary and assist activity. An example is the hydroxyl group of haloperidol. The empirical SARs could be construed to suggest that the 4-aryl piperidino moiety is superimposable on the 2pttcnylelhylamino moiety of dopamine and, accordingly. could promote affinity for D2 and D3 receptors. The long V.atkyl substituent could help promote receptor affinity and pmduce receptor antagonism activity and/or inverse ago's-en when it

Some members of the class are extremely potent antipsychotic agents and D2 and D3 receptor antagonists. El'S are

cxtremely marked in some members of this class, which may. in part, be due to a potent DA block in the striatum and almost no compensatory striatal anticholinergic block. Most of the compounds do not have the structural features

with effective anticholinergic activity. Haloper!dol, USP.

Svsien. Dv.prexsai.i.s

501

Risperidone.

Risperidone Risperdal has the structural features of a hybrid molecule between a butyrophenone antipsychotic and a trazodone-like antidepressant. It benefited

refractory psychotic patients, with parkinsonism controlled at one-tenth the dose of antiparkinsoniun drugs used with haloperidol.4° Coexisting anxiety and depressive syndromes were also lessened. It is reported to decrease the negative (e.g.. withdrawal, apathy) as well as the positive (e.g.. delusions. hallucinationsl symptoms of schizophrenia. This is reportedly a consequence of the compound's combination 5-HT2—D2 receptor antagonistic Overall the reasons for the decreased El'S and effectiveness against negative symptom are still under investigation. It is an important

atypical antipsychotic. N—O

0 F

CH3

The diphenylbutylpiperidinc class can be considered a modification of the fluorohutyrophenonc class. Because of their high hydrophobic character, the compounds are inherently long acting. Penfluridol has undergone clinical trials in the United States, and pimozide has been approved for

antipsychotie use. Overall, side effects for the two compounds resemble those produced by the lluorohutyrophenones. F

Haloperidol,

(Haldol). potent antipsychotic useful in schizophrenia and in psyassociated with brain damage. ft is frequently chosen as the agent to terminate mania and often used in therapy for Gilles de Ia Tourefle's syndrome.

•N

N—H

Pimozicie

Haloperidol

USP. Droperidol. I-( l-13-(p-fluorobenioyl)propylj- 1.2. 3.6-tetrahydro-4-pyridyl-2-benzimidazoliDroperidol,

none Ilnapsine). may be used alone as a preanesthetic neuroor a.s an antienietic. Its most frequent use is in

(Innovar) with the narcotic agent fentanyl Sublimaze) preanesthetically.

1!CH2CH2CH2—

Dropendol

11-Amlnoketones Several fl-aminoketones have been examined as antipsyThey evolved out of research on the alkaloid lobeline. The overall structural features associated with activity can be seen in the structure of niolindone. In addition to the

502

Wilson and (Jisro!d.s Textbook of Organic Medicinal and Plsarynoceutical

$-aminokctone group. there must he an aryl group posi-

Olanzapine and Quetiapine.

tioned as in molindone. It might be conjectured that the proton on the protonated amino group in these compounds Hbonds with the electrons of the carbonyl oxygen atom. This would produce a cationic center, two-atom distance, and an aryl group that could be superimposed on the analogous features of protonated dopamine.

and quetiapine (Seroquel) possess tricyclic systems cith greater electron density than chiorpromazine. They thus semble clozapine. The drugs are atypical antipsychotics.

Olanzapine (Zyprexai

Mollndone Hydrochloride.

Molindone hydrochloride. 3.ethyl-6,7-dihydro-2-methyl-5-morpholinomethyl)indolc4(511)-one monohydrochloride (Moban). is about as potent an antipsychotic as trifluopcrazine. Over.ill. side effccts resemble those of the phenothiazines.

0

I CH2—("O CL

CH3CH2

H

I

Otanzaplne

/ \—J

N Hydrochloride

Benzamldes The bcnzamides evolved from observations that the ga.stroprokinetic and antiemetic agent mctoclopramide has antipsy-

chotic activity related to D2 receptor block. It was hoped that the group might yield compounds with diminished EPS liability. This expectation appears to have been met. A H bond between the amido H and the unshared electrons of the methoxy group to generate a pseudo ring is considered important for antipsychotic activity in these compounds. Presumably, when the protonated amine is superimposed on that of protonated dopamine. this pseudo ring would superimpose on dopamine's aromatic ring.42 These features can be seen in sulpiride and renioxipride.

,,0

Ouetiaplne

Overall, these two compounds should hind less strnngl.i to D2 receptors and pemlit more receptor selectivity among receptor subtypes than typical antipsychotics. This cou!dz

count for decreased striatal D2-blocking activity. which would produce less discomfort in patients. It would be esting to see testing results of these drugs' activities over. broad range of receptors, as arc presently being for clozapinc.

With respect to the atypical antipsychotics. two long in the past may shed some light on the events The field of reuptake-inhibiting aittidepressants arose ehe only a very small structural change was made in an antipn.

0

25

CH3 Sulpieride

duce antipsychotics that are active against depressive

Remoxlpride Rentoxipride is a D2 receptor blocker.40 It is said to be ax effective as haloperidol with fewer EPS. Negative symptoms of schii.ophrenia arc diminished. The drug is classed as an atypical antipsychotic. The substituents on the aliphatic amino nitrogen and the substituents on the aromatic ring are interesting. C2H5

O\/NHCH2N

Remoxipride

chotic drug. and the new activity noted. (The atitiNcluls activity remained.) So. small changes in structure can

toms. Likewise, small changes in structure could selectivity among D2 receptors. Almost 40 years ago, it was noted that thioridnj.ine wasi less unpleasant for patients than its relativcs.4 Its system is far more nucleophilic than that of most otherdru?' The emphasis at the time, however, was to increase null gram potency by increasing D2 receptor affinity by tricyclic electron density. The experience of clozapine. sir increased electron density of the receptor-binding thus lower affinity, appears to validate the observation and appears to allow more selectivity D2 receptors. Lessening blocks on. for example. sifinial ll receptors. and possibly mesocortical D2 receptors as s. could produce drugs that are muich less unpleasant Its 1. patient. Additionally, a less intense 1)2 block could au. the effects of other blocks to make up more of the das total action (e.g.. 5-HT transporter block). Several

Chapter 14 • Central Nervous System Depressants

anhipsychotics have rings with enhanced nucleophility. 01 course. other structural features could be influencing receptar selectivity, for example, increasing stcric hindrance to receptor binding by the protonated amino group or to the rag binding.

Antimanic Agenb LITHIUM SALTS

The lithium salts used in the United States are the carbonate

leirahydrate) and the citrate. Lithium chloride is not used tvcause of its hygroscopic nature and because it is more nitahing than the carbonate or citrate to the GI tract. The active species in these salts is the lithium ion. The classic explanation for its antimanic activity is that it resembles the sodium ion (as well as potassium. magnesium, and calcium ions) and can occupy the sodium pump. Unlike the aiiu:n ion, it cannot maintain membrane potentials. Acflitters

it might prevent excessive release of neurotrans(e.g.. dopamine) that characterize the manic state.

Many of the actions of lithium ion have been reviewed." The indications for lithium salts are acute mania (often with neuroleptic agent for itnmediatc control, since lithurn is slow to take effect) and as a prophylactic to prevent cccurrence of the mania of bipolar manic—depressive illness.

Lithium salts are also used in severe recurrent unipolar depression. One effect of the drug that might be pertinent increase in the synthesis of presynaptic serotonin. Some speculated that simply evening Out transmission. preunhing downward mood swing. for example. could be a for antidepressant action. Because of its water solubility. the lithium ion is extensvcl> distributed in body water, It tends to become involved fl he ntany physiological processes involving sodium. poasiurn. calcium, and magnesium ions, hence, many side rtIccts and potential drug interactions exist. The margin of safety is low; therefore lithium should be used only when

503

an anmiepileptic drug is a drug used medically to control the epilepsies. not all of which are convulsive, in humans. A classification of the types of epilepsy has been widely accepted because its accuracy facilitate.s diagnosis, drug selection. and precise discussion of seizure The major classification types are (a) generalized seizures, which essentially involve the entire brain and do not have an appar-

ent local onset: (b) unilateral seizures, which involve one entire side of the body: (e) partial (or focal) seizures that have a focus (i.e., begin locally); (d) erratic seizures of the newborn: and (e) unclassified seizures (severe seizures asso-

ciated with high tnortaliiy such that time does not permit a precise categorization). Two major types of generalized seizures are the generalized tonic—clonic seizure (grand mal) and the nonconvulsive seizures or absence (petit mal) seizures. The typical general-

ized tonic—clonic seizure is often preceded by a series of bilateral muscular jerks: followed by loss of consciousness. which in turn is followed by a series of tonic and then clonic spasms. The typical absence seizure (classic petit mal) consists of a sudden brief loss of consciousness. sometimes with

no motor activity, although often some minor clonic motor activity exists. Major types of focal (partial) epilepsy are simple focal and complex focal seizures. A prototypic simple partial seizure is

jacksonian motor epilepsy in which the jacksonian mareh may be seen. As the abnormal discharge proceeds over the cortical site involved, the visible seizure progresses over the area of the body controlled by the cortical site. The complex partial seizure is represented by the psychomotor or temporal lobe seizure. There is an aura, then a confused or bizarre but seemingly purposeful behavior lasting 2 to 3 minutes.

often with no memory of the event. The seizure may be misdiagnosed as a psychotic episode. This is an extremely

difficult epilepsy to treat. Much effort has been made in recent years to develop drugs to control it.

Lith-

For broad consideration of how structure relates to antiepileptic activity, the classification of the epilepsies is traditionally further condensed (generalized tonic—clonic seizures. simple partial seizures, complex partial seizures, and absence seizures). The broad general pattern of structural features associated with antigeneralized tonic—clonic seizure activity is discernible for barbiturates. hydantoin.s, oxazolidincdiones. and succinimides. This SAR also applies to simple partial seizures. It applies with less certainty to complex partial seizures, which are relatively resistant to treatment. With fewer effective drug entities, overall structural conclusions are more tenuous. The other general seizure type for which a broad SAR pattern among the cited compounds can

uncarhoname (Eskalith. Lithane) and lithium citrate (Cihal-

be seen is the absence seizure. These features are cited under

Lb'S) are the salts commercially available in the United

the heading. SARs Among Anticonvulsants. Likewise, animal models characteristically discern three types of activity: activity against electrically induced convulsions correlates with activity against generalized tonic—clonic and partial seizures, and activity against pentylenetetrazole (PTZ)-induced seizures correlates with antiabsence activity. Of late, a fourth model, activity against pilocarpine and kainic acid seizures, is said to predict protection against temporal lobe epilepsy (a complex partial seizure). Each of the epilepsy types is characterized by a typical abnormal pattern in the EEG. The EEG indicates sudden. excessive electrical activity in the brain. Antiepileptic drugs

plasma levels can be monitored routinely. In the desired dose range. side eflécts can be adequately controlled.

Because of the toxicity of lithium, there is substantial inxrest in design of safer compounds. As more is learned about tham's specific actions, the likelihood of successful design

i ecrnpounds designed to act on specific targets is inarased. Actually. carhamazepine and valproic acid, which '.utsodiLtm channels, are proving to he effective.45 These :vn thugs are discussed in the anticonvulsant section.

Lithium Carbonate, USP, and Lithium Citrate.

Siec.

AN1'ICONVULSANT OR ANTIEPILEPTIC ORUGS

i

:e

customary. the terms antic'ans'uI.sant and a,muepik'pl:c used interchangeably in this discussion. Strictly speakhowever, an anticonvulsant is an agent that blocks cxproduced seizures in laboratory animals, and

is

504

tVilson

and

of Orçnmic Medicinal and P/iarmaceuucal Clie,nisirv

act to prevent. stop. or lessen this activity. The precise causes of the sudden. excessive electrical discharges may be many. and not all are understood. A working hypothesis is that there is a site or focus of damaged or abnormal and, consequently.

I

hyperexcitable neurons in the brain. These can fire excessively and sometimes recruit adjacent neurons that in turn induce other neurons to fire. The location and the extent of the abnormal firing determine the epilepsy. An addition to this theory is based on the kindling model.45 Experimentally. a brief and very localized electrical stimulus is applied to a site in the brain, with long intervals between applications. As the process is repeated. neuronal afterdischarges grow both longer and more intense at the original site and at new sites far from the original site. It is thought that changes occur in neurons at the discharge site, and these neurons in turn induce changes in neurons far from the site. Progressively more severe seizures can be induced, and these can arise from secondary foci that have been kindled far from the site of stimulation. A major mode of action of anticonvulsants can be positive allosteric modtilation of GABAA receptors. This is probably the mode of action of benzodiazepincs and a major mode of action of barbiturates. On the basis of the structure of barbiturates, some inorganic cation blocking action would be expected as wefl—voltage-gated sodium channel for phenobarbital and calcium I channel block for 5,5-dialkyl members. Oxazolidine-2.4-diones (only trimethadione remains> and succinimides appear to act via calcium T-type channel block. Some sodium channel block could be expected among phenyl-substitutcd succinimides. The major mode of action for phenytoin (and probably monophenyl substituted hydanacid. felbatoins). carbamazepine. oxcarbazepine. mate. topiramate. lamoirigine and zonisarnide is reported to be voltage-gated sodium channel block and is in accord with their structures. This does not exclude other expected actions in some of the examples.

Direct block of ionotropic glutamate receptors has so far not yielded clinically useful drugs. Some voltage-gated sodium channel drugs are reported to be antiglutaniate as well by blocking glutamate release. Side effects of direct ionotropic glutamic acid receptor blocking has been a serious problem, Because of this, present approaches are to use the modulatory route. That is. lessen ionotropic glutamate activity by (a) using drugs that act at the glyeine modulatory site on NMDA and (hI developing antagonists of members group II and group Ill melabotropic receptors and agonists of metahotropic group I glutamic acid receptors. These drugs would lower ionotropic glutaminergic activity. Adenosine. which may be an endogcnous anticonvulsant.

Structure common to anticonvrjtsanl drugs.

R'

0

NH

—o

An overall pattern in the foregoing is that R and R'

(grand mal) or partial seizures. If one of the hydrocartico substituents is an aryl group, activity tends to be toward generalized tonic—clonic and partial seizures and nil antiabsence activity.35 A conformational analysis of the aryl-containing antigrt eralized tonic—clonic agents indicates that the confonn tional arrangement of the hydrophobic groups is imporlarn,n

Barblthrates Although sedative—hypnotic barbiturates commonly disph:, anticonvulsant properties. only phenobarbital and meph. barbital display enough anticonvulsant selectivity for ascii

antiepileptics. For the structures of these agents. Table 14-2. and fordiscussion oichemical propeniessecthr section on barbiturates under agents. The metabolism of phenobarbital involves p.hydrm

ylation. followed by conjugation. Mcphobarbital is extensively N-demethylated in vivoni is thought to owe most of its activity to the metabolite phecs

barbital. In keeping with their structures, both agents tic effective against generalized tonic—clonic and panial c'

Hydantoins

Several major groups of drugs have the common structure shosvn below.

are loscr

alkyls. the tendency is to be active against absence seiruar (petit mal) and not active against generalized tonic—clonic

effects of agonists. has not yet yielded useful drugs. Elabo-

SARs Among Antkonvutsants

Oxazolidinediones

both be hydrocarbon radicals. If both R and

zures.

drug design.

I-tydantoins

Succinimides

continues to serve as a model hut, for reasons such as poor brain distribution and an array of cardiovascular

ration of roles of receptor subtypes may give leads lbr

Barbtturates

The hydantoins arc close structural relatives of the barhis rates. dil'Iering in lacking the 6-oxo group. They ate cyth monoacylureas rather than cyclic diacylureas. As a con' quence of losing a carbonyl group. they are weaker organ. acids than the barbiturates (e.g.. phenytoin pK,, = aqueous solutions of sodium salts, such as of phenyroin dium, generate strongly alkaline solutions.

Chapter 14 U ('eniral

TABLE 14-4 Anticonvulsant Hydantoin Derivatives

Name

conjugated. The compound is used against generalized seizures, but

R'5

?yimoUSP

-'

Mesonloin

H

hydroxyl group. The drug has a spectrum of activity similar to that al phenytoin. It may worsen absence seizures.

Ethotoin. 3-ethyl-5-phenylhydantoin (Peganone), is N.dealkylated and p-hydroxylated: the N-dealkyl inetabolite. presumably the active compound. is likewise metabolized by p-hydroxylation. TIre hydroxyl group is then

Substituents Rs

505

Ethotoin.

N—H

Generic Name

SvOens

R3

H

usually on an adjunctive basis. owing to its low potency. In general. agents that are not completely branched on the appropriate carbon have lower potency than their more completely branched counterparts.

CH3—

Oxazolidinedlones

CH3—CH2—

Replacement of the N-H group at position I of the hydantoin system with an oxygen atom yields the oxazolidine-2.4dione system. The oxazolidinedione system is sometimes equated with autiabsence activity, but this trophisni probably is more dictated by the fact that the requisite branched atom

The compounds have a trophism toward antigencralized eric—clonic rather than antiabsence activity. This is not an rnninsic activity of the hydantoin ring system. All of the dinically useful antigeneralized tonic—clonic compounds Table 14-4) possess an aryl substituent on the 5 position. to the branched atom of the general pharmacophore. Hydantoins with lower alkyl substituents reportoily have antiabsence activity.

Phenytoin and Phenytoln Sodium, USP. Phenytoin. 33-diphenyihydantoin (Dilantin). is the first anticonvulsant in which it was clearly demonstrated that anticonvulsant accould definitely be separated from sedative—hypnotic It is often cited as the prime example of an anticoncabant acting as a sodium channel blocker.'3 °' One effect of neuronal sodium channel block is to decrease presynaptic

°' acid release, giving anticonvulsant Another consequence is to reduce glutamate-induced isitiemic damage to neurons)'1 52 The drug is useful against if oeizurc types except absence. It is sometimes noted that he drug is incompletely or erratically absorbed from sites if alministration. This is due to its very low water solubility. Mesibolism proceeds by stereospecific p-hydroxylation of .n nromatic ring, followed by conjugation. Mephenytoin, USP. Mephenytoin. 5-ethyl-3-methyl'phenyl-hydantoin (Mesantoin), is metabolically N-dealkyted to 5-ethyl-5-phenylhydantoin, believed to be the active

Interestingly, 5-ethyl-5-phenylhydantoin. the hydan'iincounterpan of phenobarbital. was one of the first hydan. introduced into therapy. It was introduced as a sedaa-hypnotic and anticonvulnant under the name Nirvanol. it was withdrawii because of toxicity. Presumably. meph. ccyioin may be considered a prodrug that ameliorates some ci the toxicity—serious skin and blood disorders—of the active drug. Metabolic inactivation of mephenytoin and its demethyl is by p-hydroxylation and then conjugation of the

of these compounds is substituted with lower alkyls. Arylsubstituted Oxazo)lidine-2.4-diones have shown activity against generalized tonic—clonic seizures. The oxazolidined-

ione group of anticonvulsants used clinically has shrunk to one clinically useful member. Toxicities associated with the group may be the problem.

Trimethadione, USP. Trimethadione. 3.5.5-trimethyl. 2.4-oxctrolidinedionc. 3,5,5-trimethadionc (Tridione), was the first drug introduced specifically for treating absence seil.ures. It is important as a prototype structure for antiabsence compounds. Demiatological and hematological toxicities limit its clinical use. The drug is metabolized by N-demethylation to the putative active metabolite Dimethadione is a calcium T channel blocker. Dimethadione is a water-soluble and lowly lipophilic compound and thus is excreted as such without further metabolism.

CH3 R5 =

= CH,

Sucdnlmldes In view of the activity of antiepileptic agents sttch as the oxazolidine-2,4-diones, substituted succinimides (CU. replaces 0) were a logical choice for synthesis and evaluation. Three are now in clinical use.

Phensuximide, USP. Some trophisni toward antiabsence activity is attributed to the succinimide system. The —CH2— could be viewed as an a-alkyl branch condensed into the ring. Phensuximide. N-methyl-2-phenylsuccinimide (Milontin). is used primarily against absence seizures, hut it has low potency and is relegated to secondary status. The

Wilson 011(1

Textbook of Organic Medicinal and Phar,nacegitical Che,nis:rv

phenyl substituent confers some activity against generalized tonic—clonic and partial seizures. N-demechylation occurs to yield the putative active metabolite. Both phensuximide and the N-dcmethyl metabolite are inactivated by p-hydroxylation and conjugation.

at the (Z)cis-stilhene double bond. In humans, the epoxidc reportedly is converted largely to the lOS. I The epoxide is a suspect in the idiosyncratic reactions carba. mazepine may produce (e.g.. aplastic anemia). With this in

mind, compounds designed to avoid the epoxide such as oxcarbazepine (Trileptal) were developed.

CH2

Methsuxim4e

R=Q__R'=cH3

/

C=0

R'=CH3

R = C2515—. R' = CH3, A'

H

Methsuximide. N-demethylation and p-hydroxylation of parent and metabolite occur. Methsuximide, N.2-dimcthyl-2-phenylsuccinimide (Celontin), has some use against absence and complex partial seizures.

Ethosuximide. 2-ethyl-2-methylEthosuximide, USP. succinimide (Zarontin). conforms veiy well to the general structural pattern for antiabsence activity. The drug is more active and less toxic than trimethadione. It is a calcium T channel—blocking drug. Toxicity primarily involves the skin and blood. Some of the drug is excreted intact. The major metabolite is produced by oxidation of the ethyl group.

Wean and Monoacylureas The two chemical classes. ureas and monoacylureas. have a long history of producing compounds with anticonvulsant activity. The numerical yield of clinically useful compounds has not been great, however. Most of the simpler compounds have gone by the way. For convenience of grouping. carbamazcpine and oxcarbazepine can be considered N.N-diacyl-

Oxcarbazeplne

Oxcarbazepine is reduced to the monohydroxy compour4.

undoubtedly stercospecifically. The monohydroxy corn pound is considered the major active melabolite. The drug is used against partial seizures. The major mechanism of action is sodium channel block.

Miscellaneous Agents Primidone. Primidone. 5-ethyldihydro-5-phenyl.4,fs (IH.5H)-pyrimidinedione (Mysolinc). is sometimes scribed as a 2-dcoxybarhiturate. Ii appears to act as such

through conversion to phcnobarbital and to lonyldiarnide The efficacy is against all types ii seizures except absence. The agent has good sakty but rare serious toxic effects do occur.

/\o

ureas. H

carbamazeplne. USP. Carbamazepine. 5H-dibenzlb.fllazepine-5-carboxamide (Tegretol). for SAR discussion purposes, can be viewed either as an ethylene-bridged 1.1diphenylurea or an amido-substituted tricyclic system. The two phenyls substituted on the urea nitrogen fit the pattern

of antigeneralized tonic activity. The overall shape of the molecule suggests the mode of action, sodium channel block.

Carbamazepine is useful in generalized tonic—clonic and partial seizures.

O==C—NH2 Carbamazepine

The drug has the potential for serious hematological toxic-

ity, and it is used with caution. Metabolism proceeds largely through the epoxide formed

Pnmidone

Vaiproic Acid.

Many carhoxylic acids have anticonsU

sant activity, although often of low potency, possibly Inpi" because extensive dissociation at physiological pH prodas. poor partitioning across the blood—brain barrier. acid. 2-propylpentanoic acid (Depakene). has good and is used against several seizure types. They include cal and atypical absence seizures and absence seizure generalized tonic—clonic seizure. Mechanistically, the la is a sodium channel blocker. This is in accordance wnhq structural features. It is also reported to increase els. again in conformity with its structure. Metabolism conjugation of the carboxylic acid group and oxidatka one of the hydrocarbon chains. Many of the side effcct'rr

mild. A rare, but potentially fatal, fulminate hepatitis caused concern, however. One tends to look to the

atom a to the carboxyl acid as being labile and a toxiphore.

Chapter 14 • Central Nen'ous

Depressants

507

Lamotrigine.

Lamotrigine (Lamictal) has been found effective against refractory partial seizures. It is said to act by blocking sodium channels and preventing glutamate reIt is a member of a group of drugs that reduce gluta-

CH 3CH2CH2

mate release and thus reduce neuronal cell death in ischemia.

Vaiproic Acid

Despite the fact that gabapentin (Neuroatin) is a relative of GABA with increased hydrophobic character, its mechanism of action does not appear to involve an interaction with GABAA receptors. A binding site on calcium channels has been identified, but the mode of action of the drug is considered unclear. The drug is said to have

One trial with lamotrigine did not detect slowing of the progression of amyotrophic lateral sclerosis (ALS). Another member of the group (sodium channel blockers with antiglutamate effect), riluzole (Rilutek) (2-amino-6-(Irifuroethoxy)benzothiazole) is used to slow progression. The bottle-stopper shape of both drugs is readily apparent.

a good pharmacokinctic profile and to cross the blood—brain

barrier well, it was introduced for adjunctive therapy of refractory partial seizures and, secondarily, generalized NH2

Ionic—clonic seizures. It was studied as a single drug therapy for various

Lamotrigine

and Topiramate (Topamax).

Zonisamide H2N

OH

Gabapenrin

(Gabitril).

A glance at tiagabine's structure cuggeats an uptake inhibitor. Reportedly, it blocks GABA rcuptake as a major mode of its anticonvulsant activity. its

Zonisamide and Topiramate have, respectively, the sulfonamide and sulfate amido as the small diameter end polar group and an extensive hydrophobic group as the large diam-

eter end of the bottle stopper. Both are sodium channel blockers. Zonisamide also blocks calciuin-T channels and Topamax increases the effect of GABA and antagonizes glutamate kainic acid/AMPA receptors. Each of the drugs is employed adjunctively against partial seizures.

iw is against partial seizures. .COOH

(Na H2N

2 /\\ 0

Zonisarnide

l'iagabine Felbamate.

Felbamate (Felbalol) has been used sue-

in refractory patients with generalized tonic—clonic

and complex partial seizures. The mechanism of may involve an interdction with the strychnine-insenreceptor on the NMDA receptor.°t' It is also a sodium blocker. The drug is associated with a serious risk anemia. It is used with extreme caution after other criconvulsants have been tried and a careful risk-to-benefit has been made.

Felbamate

Topiramate

Benzodlazeplnes For details of the chemistry and SARs of the benzodiazepines, see the discussion of anxiolytk—sedative—hypnotic drugs. Among the present clinically useful drugs. the structural features associated with anticonvulsant activity are identical with those associated with anxiolylic—sedative—hypnotic activity.22 Animal models predict that benzodiazepines are modestly effective against generalized tonic—clonic and partial seizures and very highly active

508

Wilson and Gi olds Texil,ook of Organii' Medici,wI and PI,arn,aceiaical Chemistry

against absence seizures. This difference in seizure control tropism differs markedly from that of the barbiturates, hydantoins. and most other chemical compounds when they are aryl- or diaryl-subslituted. Despite the high effectiveness of benzodiazepines as a group in animal models, only a few benzodiazepines have achieved established positions in anticonvulsant therapy. Because selective anticonvulsants should be attainable among agents acting at GABAA benzodiazepine allosteric modulatory sites, the number may increase in the future. A problem with the benzodiuzepines has been decreased effectiveness over time. When physiological adaptation of this type occurs, it usually happens with sedative agents. If sedation were divorced from anticonvulsant action, possibly the latter might be sustained.

clonazepam. USP.

Clonazepam 5-(2-chlorophenyl)-3(Kionopin). dihydro-7-nitro-2H- I .4-benzodiazpin-2-one partially selective at bcnzodiazepine allosteric binding sites on GABAA receptors, is useful in absence seizures and in myoclonic seizures. Tolerance to the anticonvulsant effect

often develops, a common problem with the benzodiazepines. Metabolism involves hydroxylation of the 3 position. followed by glucuronidation and nitro group reduction, followed by acetylation.

I/I

H

0

N—C

C=N

ON 2

Clortazepam

galed nit channels as molecular sites ol alcohol and anesthelic action

Ads. Btochcm. Psychopharmaciil. 47.335, 1992.

5. Miller. K. W,: General anesthetics, in Wolff. M. D. ted.,. fluigci'

6.

Medicinal Chcotislry, part III. 4th ed. Ness York. John Wiley & Sew 1981. p. 623 (and referetices therein). F. H.. F,ynng. H.. mid i'olissar. M. 3.: The Kinetic Basiic)

Molecular Biology. New York. John Wiley & Sons. 1954. 7. Cohen, F.. N.: Br. J. Anacslh. 511:665,

978.

8. Stock. J. 0. I... and Strunin. L.: Anesthesiology 63:424. 1985. 9. Cousins, M. 3.. and Marie, R. L.: JAMA 225:1611. 1973. 10. Hiti. B et at.: J. Pliarinacul. Esp. 'flier. 2(13:193. 1977. II. Holiiday. B. A.. et at.: Anesthesiology 43:325. 975. 12. Willer.J. C.. flergeret. S.. Gaudy, J. H.. and l)authier. C.: Anesthesri ogy 63:467. 1985. 13. Takaki. K. S.. and Eppcrson. S. R.: Annu. Rep. Med. Cheni. 3441 1999.

14. Huang. i-K., and Jan. C.-R.: Life Sci. 68:611. 2(88). 15. Weinherger. B. K.: N. lingl. J. Mcd,344:l247. 2001, 6. Xue. II.. ci al.: J. Mcd. Cheni 44:1883. 20(11. 17. Xue, H.. ci al.: J. Mol. Bind. 296:739. 2000. 18. Renard. S.. et at.: J. Blot. Client. 274:13370, 1999. 19. Buhr. A.. ci at.: Mul. Pharniacol. 49:1080. 19%. 20. Buhr. A.. ci al.: Mol. Pharmacol. 52:672, 1997, 21. Bohr, A.. et at.: 3. Neurochem. 74:1310,2(88). 22. Slernbach, L. H.: In Garatlini. S., Mi,ssini, E.. and Randall, 1. 0.ieki The Benzodiazepines. New York. Raven Press. 1972. p. I. 23. Chuldress. S. J.: Antianxiety agents. In Wolff. M. B. (nil. Qarg& Medicinal Chemistry, part lIt. 4th ed New York. John Wile) and Sir 1981, p.981. 24. Grecnhlatt, 0. J.. and Shader. K. I.: Bcnzodiaeepines in Clinical Ps. 11cc. New York, Raven Press, 1974. p. 7 (and references thcreinm 25. Greenblati. D. .1., Shader. K. I.. and Abernathy. D. R.: N. EngI. 1. M:1 309:345, 410, 1983.

26. Daniels. T. C.. and Jorgensen. F. C.: Central nervous system kr sums. In Docrge, R. F. ted.). Wilson and CIissold's Tc,tlbook of Medicinal and Pharmaceutical Chemistry. 8th ed. Philadelphut, 3.

Ltppincott. 1982. p. 335. 27. Berger. F. M.: Meprobamate and other glycol derivatives. In U,ij E.. and Forrest. I. S. teds.). Psychotherapeulic Drugs, pail IL Ii:. York. Marcel Dekker. 1977. p. 1089. 28, Cram. 0. J.. and Hammond. 0. S.: Organic Chemistry. 2nd ed. 5:: York. McGruw'HiIl, 1964. p. 295. 29. Mackay. F. J.. and Cooper. J. R.: J. Pharmacol. Exp. The,. 1352' 1962.

Dlazepam.

For details on diazepam (Valium) see its

discussion under anxiolytics and sedative—hypnotic agents. The drug is mainly useful in treating generalized tonic—clonic status epilepticus. which is an ongoing and potentially fatal generalized tonic—clonic seizure.

chlorazepate.

See the detailed discussion of chlorazepate (Tranxene) in the sedative—hypnotic—anxiolytic section. U.s principal anticonvulsant use is adjunctively in complex partial seizures.

Overall, there has been progress in recent years in the intro-

duction of antiseizure drugs. Most of the progress has involved voltage-gated sodium channel blocking Good reviews arc available.57' REFERENCES I. Strange. p. (1: Phamiacol. Rev. 53:119. 2001. 2. Longoni. B.. and Olsen. K. W.: Sludie'i on the mechanism at interaction of with GABA5 receptors. Mv. Biochem. Psychophurmai• ciii. 47:365. 1992. 3. Chebib. M.. and Johnston. G. A. R.: 1. Med. Cliem. 43:1427. 2(885.

4. Weight. F. F.. Aguayo. L. 0., While. ci. ci at.: GABA- and glutamate'

30. Rowley. M.. Bristow. L. J.. atid Hutson. P. H,: J. Med. Chem. 44r 2tX)l. 31. Karlsson, H.. et il.: Proc. Natl. Acad. Set. U. S. A. 98:4634. 2151 32. Lewis. 0. A.: Proc. NatI. Acad. Sci. U. S. A. 98:4293. 2)88). 33. Felder. C. C.: Life So. 68:2605, 2001. 34. Yeotnaits. i. ci al.: Life Sd. 68:2449. 2001. Cook. L.. Tedeschi. 0. H.. and Tedcshi, R. F.: Awwn 35. Gordon hirsch. 13:318. 1963. 36. Horn. A. S.. and Snyder. S. H.: Proc. Nail. Aced. Sci. U. S. A I' 2325, 1971.

37. Miller. 0. 0.. ci al.: I. Med. Chem. 30:163. 1987. 38. Kaiser. C.. and Setler. P.: Anlipsychotic agents. Itt Wolit'. M. F::' Burger's Medicinal Chemistry, part Ill, 4th ed. Nen York. John ItI:. and Sons. 1981. p. 859. 39. Janssen. P. A. J.. and Van Bever. W. F. M.: Bttlyrnphenniccaali phenylbutylamines. In Usdin. F... and Forresl. I. S. (eds.t. Podieth.-. peutic Drugs, part II. New York. Marcel Dekker. 1977. p. 1169 41). Howard. H. R.. and Seeger. T. F.: Annu. Rep. Med. Cltetn. 2539. (and references therein).

41. Chen. X.-M.: Annu. Rep. Med. Chain. 29:331. 1994. 42. van de Watcrt,eemd. II.. and Tecta. B.: 3. Mcd. Chem. 26:24)). II" 43. Potter. W. 1. and Hisllister, L. F..: Antipsychotic agents and title

In Katiung. B. C. (cdl. Basic and Clinical

85i

New York. Lange Medical Books/McGraw.HllI. Medical PSNi'l.. Division, 2001. p. 478. 44. Entriclt. H Aldenltolf. J. B.. and Lux. Ii. I). )eds nisnis iii the Action of Lithium. Symposium Proceedings. Amerimit Excerpta Medica. 1981. 45. 1.eysen, 0.. and Pinder. R. M.: Annti. Rep. Med. Cheini. 29:1, 46. Gastatit, H.. and Broughtort. R.: In Radoaco-Thomas. C. led.): AiL' .

Chapter 14 • Ceiiiriil ,Vi'rrogg.i System Depre.v.com.c ulsani Drugs. viii. I - Inlernaijonal Etrcycliipeitvi iii l'harniacoiogy and Therapeutics. New York. Perganion. 973. p.

Ciniinussion on (Iassilicaiion and Terminology oI the lnternaiioiial

509

Med. Cheni 33:51. 1998 58. Anger. 1.. Madge. I). 3.. .MnIla, M.. and Riddall. 0.: 3. Med. Client. 57. M:nlge. I). 3: ,%nnn. Rep.

44:115. 2(8)1.

League Against Epilepsy: Epilepsia 22:489. 1981.

Wada. J. A. (cdi: Symposium: Kindling 2.

York. Raven l'ress.

1991

SELEcTED READING

Spiehnan. SI. A.: In Hanung. W. II. iedj. Medicinal I. p. Cheiniswv. vol. 5. New York. John Wiley & Sons, 1961, Wong. M. G . IX'hnu. 3 A.. and Andrew'.. P. R.: J. Med. ('hem. 29:

Chebib. M.. and Johnston. C.. A. R.: ligund gated ion channels. tnedicinai ehemistr) and molecular hiology. 3. Med. Chem.

562. 1996. Iuigge. C. F.. and Boxer. P. A.: Anna. Rep. Med. ('hem. 29:13, 1994. Knoplel, T., Knhut. R.. and Allgeier. It: J. Med. Cheun. 38:1417. 1995.

Cosliurul. N.. I). P.. McDonald. I. A.. and Schweiger. E. 3.: Recent pussgress hut anihepileptuc drug research. Annii. Rep. Med. Chem. 33:61. 1998.

(Iivse.

W. J.. and

Prey. Ft. H,. and l)rewelimer. B. II.: Arch.

Pttannacinlyn. TIter.

193:181. 1971.

Roweley, M., Ilrkliiw. L. 3.. and Hnusiin. P. H.: Cuineni and novel up. preaches to the drug treatment of schizophrenia. 3. Med. Chem. 44: 477,

Refined. (3.. Berth. (3.. ('hiappe. C., eta).: 3. Med. Chent.3(1:768, 1987. Spinks. A.. aiid Waring. W. S.: In Ellis, (3. P. and Wesi. U. B. (cdv.). Prngressin MeulicinalCiuemisury. viii. 3. Washington, IX'. llnuiersvorth. 963. p. 261 Cusfiurd. N. 1).

43:1427. 2(88).

P..

ci

al

:

Anna. Rep. Med. Client. 33:61. 1998.

21811.

Strange. P. (3.:

Aniipsyehodc dnigs: importance of dopamine receptors for uherapentic actions aiid side elTeew. Phannaeol. Ren.

niecltanisnus of

53:19. 2)811. Weinherger. D. R.: 3.

Anxiety at

Med. 344:1247. 2001.

lie loitnier iu( molecular

medicine. N. Engi.

CHAPTER 15 Central Nervous System Stimulants EUGENE I ISAACSON

This chapter discusses a broad range of agents that stimulate the central nervous system (CNS). The analeplies classically arc a group of agents witha limited range of use because

Pent ylenetetrazole. Pentylenetetrazole. 6.7.8.9-tetra. hydro-5H-tctrazolof I.5-a/azepine. I ,5-pentamethylcnecct. razole (Metrasol), has been used in conjunction with the

of the general nature of their effects. The inethylxanthines have potent stimulatory properties, mainly cortical at low doses but with more general ellects as the dose is increased. The central agents amphetamine and close relatives have alerting and antideprcs.sant properties hut medically arc used more often as anorexiants. The antidepressant drug.s are used most frequently in depres-

electroencephalograph to help locate epileptic foci. It is used

sive disorders and can be broadly grouped into the monoamine oxidase inhibitors (MAOI5). the monoamine reuptake inhibitors, and agents acting on autoreceptors. A small group of miscellaneously acting drugs. which includes a number of hallucinogens. cocaine, and cannabinoids. concludes the chapter.

sive drugs, including picroloxinin.

ANALEPTICS

Modafinil.

The traditional analeptics area group of potent and relatively nonselective CNS stimulants. The convulsive dose lies near their analeptic dose. They can be illustrated by picrotoxinin and pentylenetetrazole. Both are obsolete as drugs but remain valuable research tools in determining how drugs act. Newer agents. modafinil and doxapram, are more selective and have cisc in narcolepsy and as respiratory stimulants.

as a laboratory tool in determining potencies of anticonvulsant drugs in experimental animals. The drug acb as a convulsant by interfering with chloride conductance: It binds loan allosteric site on the GABAA receptor and act' as

a negative modulator. Overall, it appears to share

similar

effects on chloride conductance with several other consul.

Pontylenetetrazole

Modalinil (Provigil) has overall wakeful

ness-promoting properties similar to those of central thomimetics. It is considered an atypical a1-norepinephrirc (NE) receptor stimulant and is used to treat daytime clcqir ness in narcolepsy patients. Adverse reactions at therapeutk doses are reportedly not severe and may include ness, anxiety, and insomnia.

Pkrotoxin.

Picrotoxinin. the active ingredient of picrotoxin, has the following structure:

/ OH' 0

/

0 = C- -. Picroioxnrn

According to Jarhoe ci al..' the encircled hydroxylactonyl moiety is mandatory for activity, with the encircled 2-propenyl group assisting. Picrotoxinin exerts its effects by interfer-

ing with the inhibitory eflècts of y-aminobutyric acid (GABA) at the level of the GABAA receptor's chloride chun-

nd. The drug is obsolete medically. Pharmacologically, it has been useful in determining mechanisms of action of sedative—hypnotics and anticonvulsants. Butyrolactones bind to

the picrotoxinin site.

510

Modatinil

Doxapram Hydrochloride, USP.

Doxapram. l.clhy

4-(2-niorpholinoethyl)-3.3-diphenyl-2-pyrolidinone hydn. chloride hydrate (Dopram), has an obscure molecular anisni of action. Overall, it stimulates respiration by xii on peripheral carotid chemoreceptors. It has use as a respr. tory stimulant postanesthetically. after CNS depressantdft overdose, in chronic obstructive pulmonary diseases. aisi the apneas.

Chapter IS • Central Nenou.c System Simm/ants

I'

0

(

C1

'H20

CH2CH3 Doxapram Hydrothtoride

511

been little studied. At high doses, the tendency to produce convulsions is greater for theophylline than for caffeine. In addition to being conical stimulants. theophylline and caffeine are medullary stimulants, and both are used as such. Caffeine may be used in treating poisoning from CNS-depressant drugs, though it is not a preferred drug. The important use of theophytline and its preparations in bronchial asthma is discussed elsewhere. Caffeine also is reported to have valuable bronchodilating properties in asthma. Finally, because of central vasoconstrictive effects, caffeine has value in treating migraine and tension headaches

METHYLXANTHINES naturally occurring methyixanthines are caffeine, the-

The

and theobrornine. See Table 15-I for their strucsirs and occurrence and Table 15-2 for their relative potendes.

is a widely used CNS stimulant. Theophylline medical use as a CNS stimulant. hut its CNSproperties are encountered more often as some-

Caffeine some

ants severe, and potentially life-threatening, side effects of ts use in bronchial asthma therapy. Theobromine has very in)c CNS activity (probably because of poor physicochemicat properties for distribution to the CNS).

Caffeine is often used as it occurs in brewed coffee. )rewcd tea, and cola beverages, in most subjects. a dosage t185 to 250 mg of caffeine acts as a conical stimulant and clear thinking and wakefulness, promotes an abillv to concentrate on the task at hand, and lessens fatigue. Ac the dose is increased, side effects indicating excessive $mutation (e.g.. restlessness, anxiety, nervousness, and become more marked. (They may be present saying degrees at lower dose levels.) With further intirases in dosage, convulsions can occur. A review of the of caffeine in the brain with special reference to :xtors that contribute to its widespread use appears to be

and may have actual analgesic properties in the latter use. The CNS-stimulating effects of the methylxanthines were once attributed to their phosphodiesterase-inhihiting ability. This action is probably irrelevant at therapeutic doses, Evidence indicates that the overall CNS-stimulant action is related more to the ability of these compounds to antagonize adenosine at A1 and A2A receptors.3" All of the roles 01' these receptors are still under study, The adenosine receptor 1-9 subtypes and their pharmacology have been Problems with the present compounds. such as caffeine and theophylline. are lack of receptor selectivity and the ubiquitous nature of the various receptor suhtype.s. Caffeine and theophylline have pharmaceutically important chemical properties. Both are weak l3ronsted bases. The reported pK, values are t).8 and 0.6 for cat't'eine and 0.7 for

theophylline. These values represent the basicity of the imino nitrogen at position 9. As acids, caffeine has a above 14. and theophyllinc. a pK,, of 8.8. In theophylliute. a

proton can be donated from position 7 (i.e.. it can act as a Bronsted acid). Caffeine cannot donate a proton t'rom position land does not act as a Brønsted acid at pH values under 14. Caffeine does have clectrophilic sites at positions I. 3. and 7. In addition to its Brønsted acid site at 7. theophylline has clectrophilic sites at I and 3. In condensed terms, both compounds are electron-pair donors, but only theophylline is a proton donor in most pharmaceutical systems. Although both compounds arc quite soluble in hot water (e.g.. caffeine 1:6 at 80°C). neither is very soluble in water at room temperature (caffeine about 1:40. theophyllinc about

Jciinitive!

The CNS effects of theophylline at low dose levels have

1:120). Consequently. a variety of mixtures or complexes designed to increase solubility are available (e.g.. citrated caffeine, caffeine and sodium bcnzoatc. and theophylline ethylenediansine compound laminophylline I). theopliyl' Caffeine in blood is not highly protein bound. Differences in the substituent at line is about

TABLE 15-1

the 7 position may he involved. Additionally, caffeine is

Xanthme Alkaloids o

A"

Relative Pharmacological Potencies of the Xanthines TABLE 15—2 A,

Respir-

Xanthine

CNS

(A, A' & A= H) Xanthlne Compound

R CO3

CH3 H

R' CO3 CHa CH3

R" CH3 H

CH3

Common Source Colfoc. tea Tea Cocoa

CaffeIne Theophyllttie Theobromlne

atory

Stimu-

Stimu-

latlon

latlen

1' 2 3

2

t

Skeletal

nary Cardiac Muscle DlIa- Stimu- Stimurests tatlon lation latton Diu3 2

3

3

1

1

2

2

I

2 3

512

Wilson and Gisvold's Textbook of Organic Medicinal and Pharn,areu:ieal Cla'n,issrv

more lipophilic than theophylline and reputedly achieves higher brain concentrations. The half-life of caffeine is 5 to

8 hours, and that of theophylline, about 3.5 hours. About 1% of each compound is excreted unchanged. The compounds are metabolized in the liver. The major metabolite

of caffeine is I -methyluric acid, and that of theophylline. 1.3-dimethyluric acid)° Neither compound is metabolized to uric acid, and they are not contraindicated in gout.

CENTRAL SYMPATHOMIMETIC AGENTS (PSYCHOMOTOR STIMULANTS) Sympathomimetic

agents, whose effects are manifested

mainly in the periphery, arc discussed in Chapter 16. A few simple structural changes in these peripheral agents produce compounds that are more resistant to metabolism, more nonpolar. and better able to cross the blood—brain barrier. These effects increase the ratio of central to peripheral activity, and the agents are designated, somewhat arbitrarily, as central .cvnipathomirnezic agents. In addition to CNS-stimulating effects, manifested as ex-

citation and increased wakefulness, many central sympathomimetics exert an anorcxiant effect. Central sympathomi-

metic (noradrenergic) action is often the basis for these effects. Other central effects, notably dopaminergic and serotoninergic effects, can be operative, however.' l In some agents, the ratio of excitation and increased wakefulness to anorexiant effects is decreased, and the agents are marketed as anorexiants. Representative structures of this group of compounds are given in Table 15-3. The structures of the anorexiants phendimetrazine and sibuiramine and the alertins agents methylphenidate and pemoline. useful in aliention-deficient disorders, are given in the text. Structural features for many of the agents can be visualized easily by considering that within their structure they

Sympathomlmetics With SIgnIfIcant Central Stimilant ActivIty TABLE 15-3

Base Structure

Generic Name

creases activity. Mono-N subslituents larger than methyl dt-

crease excitatory properties, but many compounds anorexiant properties. Consequently. some of these ageas are used as anorexiants, reportedly with less abuse than amphetamine. There can be some departure 1mm the basic amine structure when compounds act by indirect structure. has gic mechanisms. A ever, can be visualized in such compounds. The abuse potential of the more euphoriant and stitnub tory of the amphetamines and amphetamine-like dnigs well documented. They produce an exceedingly addiction. Apparently. both a euphoric "high" lated to effects on hedonistic D2 receptors) and a ponvi phone depression (especially among amine-depleting drug-, contribute to compulsive use of these agents. Abuse

drugs (especially methamphetamine) in recent yearn reached disastrous proportions. Recognized medical indications for dextroamphetarec and some very close congeners include narcolepsy. Palan

Amphetamine

son's disease, attention-deficient disorders, and. not the preferred agents for obesity. 'appetite suppression.L some conditions, such as Parkinson's disease, for which

Mothamphetamine Phentormine Benaplietamine

H

H

H

CH.JH

H

H

Diothytpwpion

0

H

CH3 CR2C6H5 C2H,,

H

CH3

C—C—NH

Fenfluaunine CF3

Catbon5i

contain a fi-phenethylamine moiety, and this grouping can give some selectivity for presynaptic or postsynaptic drenergic systems. f3-Phenethylamine. given peripherally. lacks central activity. Facile metabolic inactivation by monoamine oxidases (MAOs) is held responsible. Branching with lower alkyl groups on the carbon atom adjacent (a) to the amino nitrogen increases CNS rather than peripheral activity (e.g.. amphetamine, presumably by retarding metabolisini. The a branching generates a chiral center. The dextrolS, isomer of amphetamine is up to 10 times as potent as the levo(R) isomer for alerting activity and about twice as a psychotomimetic agent. Hydroxylation of the ring hydroxylalion on the carbon (to the nitrogen) activity, largely by decreasing the ability to cross the blood—brain barrier. For example. with a /3-01-I. has about Il 100th the ability to cross la blood—brain harrier of its deoxy congener. amphetamine. Halogenation (F. Cl. Br) of the aromatic ring decreases sympathomimetic activity. Other activities may increase. Chloroamphetamine has strong central serotoninergic activity (and is a neurotoxin. destroying serotoninergic neumn' in experimental 'animals).'2- 13 Methoxyl or methylenedioxy substitution on the tends to produce psychotomimetic agents. pism for dopaminergic (D2) receptors. N-methylation increases activity (e.g.. compare meihan, phetamine with dextroamphetamine). Di-N-methylation

H

H

CHnCH3

main use is to decrease rigidity, the antidepressant elki of dextroamphetaminc can be beneficial. It is also an effective antidepressant in terminal malignancies. most all cases of depression. and especially in majordeprvs sive disorders of the unipolar type, however. mine has long been superseded by other agents. nolabl} IL MAOIs and the monoamine reuptake inhibiting anhidepro Saflts. The compounds and their metabolites can have

multiple utctions. In a fundamental sense, the structural for action is quite simple. The compounds and their mcuhlites resemble NE and can participate in the various neurst.

Chapter 15 • and postsynaptic processes involving NE. such as synthesis, release. reuptake. and presynaptic and postsynaptic receptor

C'e',:gruI Nervous Svstenu Ssiu,ulwns

513

been reported to be the major active metaholite involved in NE and DA release.'4

activation. Also, because dopamine (DA) and, to a lesser cxtent. serotonin (5-hydroxytryptamine 15-HTI) bear a strucurat resemblance to NE. processes in DA- and 5-HT-aeti-

systems can be atTected. To illustrate the potential complexity. the rcceptor activations that can be associated auth just one parameter, reduction in food intake, reportedly are 13a. 5HTffl. 5HT,A. 5HT,c. D1. and D2. PRODUCTS

Amphetamine Sulfate. USP. Amphetamine. (± )- I (Benzedrine), as the racemic mixture has a higher proportion of cardiovascular effects than dextro isomer. For most medical uses, the dextrorotatory corner is preferred.

Methamphetamine

Hydrochloride.

Methamphela-

mine. (+ )- I -phenyl-2-methylaminopropane hydrochloride desoxyephednnu, hydrochloride (Desoxyn). is the N-methyl analogue of dcxtroamphetamine. It has more marked central and less peripheral action than dcxtroamphctamine. It has a very high abuse potential. and by the intravenous route, its salts are known as "speed." The overall abuse problem presented by the drug is a national disaster. Medicinally accept. able uses of methamphetamine are analogous to those of dextroamphetamine.

Phentermine Ion-Exchange Resin and Phentermlne Hydrochloride, USP. The free base is a.a-dimethylphenethylamine. I -phenyl-2-methylaminopropane. In the resin

Dextroamphetamine Sulfate, USP, and Dextroamphetamine Phosphate. Dextroamphetamine. (+ )-(S)methylphenethylamine. forms salts with sulfuric acid (DexeJñne and with phosphoric acids. The phosphate is the more water-soluble salt and is preferred if parenteral administra(on is required. The dextrorotatory isomer has the (S) conflguration and fewer cardiovascular effects than the levorotakruy (R) isomer, Additionally, it may be up to 10 times as potent as the (R) isomer as an alerting agent and about twice potent a psycholomimetic agent. Although it is a more potent psychotounimetic agent than the (R) isomer, it has a better ratio of alerting to psychotomimetic effects.

The major mode of action of dextroamphetamine is rerose of NE from the mobile pool of the nerve terminal. Other mechanisms. such as inhibition of uptake. may make a mall conuibution to the overall effects. The alerting actions rtlaue to increased NE available to interact with postsynapnic sceptors (en1). Central fl-receptor activation ha,s classically tv-en considered the basis for most of the anorexiant effect.

The psychotomimetic effects are linked to release of DA iisl activation of posisynaptic receptors. D2 and mesolimbic Dc rereptors would be involved. Effects on 5-HT systems iso have been linked to some behavioral effects of dextro-

_'nphetamine. Effects via 5-HT receptors would include 9ff5 receptors and, theoretically, all additional receptors trough 5HT7.

Destroamphetamine is a strongly basic amine, with values sotu 9.77 to 9.94 reported. Absorption from the gastrointesoral tract occurs as the lipid-soluble amine. The drug is not citensively protein bound. Varying amounts of the drug are

twueted intact under ordinary conditions. The amount is under conditions of alkaline urine. Under eon:i(ons producing systemic acidosis. 60 to 70% of the drug a excreted unchanged. This fact can be used to advanin treating drug overdose. Thc n-methyl group retards, but does not terminate. mebolismby MAO. Under most conditions. the bulk ofa dose

is metabolized by N-dcalkylation to and ammonia. Phenylacetone is degraded fur-

preparation (lonamin). the base is bound with an ion-exchange resin to yield a slow-release product; the hydrochloride (Wilpowr) is a water-soluble salt.

Phentermine has a quaternary carbon atom with one methyl oriented like the methyl of(S).amphelamine and one methyl oriented like the methyl of (RI-amphetamine, and it reportedly has pharmacological properties of both the (R) and (S) isomers of amphetamine. The compound is used as an appetite suppressant and is a Schedule IV agent, indicating less abuse potential than dextroamphctamine.

Benzphetamine Hydrochloride.

Benzphetamine hydrochloride. (+ )-N-benzyl-N.a-dimethylphenethylamine hydrochloride. ( + )- I -phenyl-2-(N-methyl-N-bcnzylaminc)propane hydrochloride (Didrex). is N-benzyl-substituted

methamphetamine. The large (benzyl) N-substitucnt decreases excitatory properties, in keeping with the general structure—activity relationship (SAR) for the group. Anorexiant properties are retained. Classically, amphetamine-like

drugs with larger than N-methyl substituents are cited as anorexiant through central /3 agonism. No claims for selectivity among fl-receptor subtypes have been made in such citations. The compound shares mechanism-of-action characteristics with methylphenidate. Overall, it is said to reduce appetite with fewer CNS excitatory effects than dextroamphetamine.

Diethylpropion Hydrochloride, USP.

Because it has two large (relative to I-I or methyl) N-alkyl substituents. diethylpropion hydrochloride. I -phcnyl-2-diethylaminopropan-I-one hydrochloride (Tenuate. Tepanil), has fewer sympathomimetic, cardiovascular, and CNS-stimulatory effects than amphetamine. It is reportedly an anorexiani agent that can be used for the treatment of obesity in patients with hypertension and cardiovascular disease. According to the generalization long used for this group of drugs, increasing N-alkyl size reduces central a1 effects and increases /3 effeels, even though the effects are likely mediated principally by indirect NE release.

bet Ii) Isenwoic acid.

animals, about 5% of a dose accumulates iihc brain, especially the cerebral cortex, the thalamus, and at corpus callosum. It is first p-hydroxylaled and then (3-

to produce p-hydroxynorephedrine, which has

Fenfluramine Hydrochloride.

Fenfluramine hydrochloride. (± )N-ethyl-a-methyl-nu-(trifluoromethyl)phencthylamine hydrochloride (Pondimin), is unique in this group

of drugs, in that it tends to produce sedation rather than

514

Wilson and Gisvnki's Textbook of Organic Medicinal and Phar,nace,aica! C'hemistrv

excitation. Effects are said to be mediated principally by central serotoninergic. rather than central noradrenergic. mechanisms. In large doses in experimental animals, the drug is a serotonin It was withdrawn from human use after reports of heart valve damage and pulmo-

keted compound and is about 400 times as potent as the ervthro racemate.'7 The absolute configuration of each of the threo-methylphenidate isomers has been determined.'5 Considering that the structure is fairly complex (relative to amphetamine). it is likely that one of the two components

nary hypertension. From its structure, more apolar or hydrophobic character than amphetamine, tropism for scrotoniner-

of the ;i,reo racemate contains most of the activity. Evidence

gic neurons would be expected. Likewise, the structure

principally in the behavioral and pressor effects of the racemate.1C As is likely with many central psychomotor lants. there are multiple modes of action. Methylphenidate. probably largely via its p-hydroxy tnttabolite. blocks NE reuptake, acts as a posisynapric agonist. depletes the same NE pools as reserpine. and has effects on dopaminergic systems, such as blocking DA reupluke. Methylphenidate is an ester drug with interesting pharina. cokinetic properties arising from its structure. The pK, sal ues are 8.5 and 8.8. The protonated form in the stomach reportedly resists ester hydrolysis. Absorption of the intact drug is very good. After absorption from the gastrointestinal tract, however. 80 to 90% of the drug is hydrolyzed rapidly to inactive ritnlinic acid.aul (The extent of hydrolysis may about 5 times that for ( +) versus )Another 2 to the racemate is oxidized by liver microsomes to the macinc cyclic amide. About 4% of a dose of the racemate reportedli reaches the brain in experimental animals and there is hydroxylated to yield the putative active metabolite. Methylphenidate is a potent CNS stimulant. Indication' include narcolepsy and attention-deficit disorder. The stoic tare of the (2R,2'Ry isomer of the threo racemic mixture is shown.

Suggests an indirect mechanism. If an indirect mechanism were operative, then all postsynaptic 5-I-IT receptors could be activated. Evidence from several studies indicates that the and the 5HTw receptors are most responsible for the satiety effects of 5-H'!'. 5-HT may also intluence the type

of food selected (e.g.. lower fatter food intake).'' The (+ I isomer. dexfenfluramine (Redux). has a greater tropism for 5-HT systems than the racemic mixture. It. too, was withdrawn because of toxicity.

Phendimetrazine Tartrate, USP.

The optically pure

compound phendimetrazine tartrate. (2S.3S)-3.4-dimethyl2-phenylmorpholine-t.-( + )-tarlrale (Plegine). is considered an eftèctive anorexiant that is less abuse prone than amphetamine. The stereochemistry of (+ )phendimetrazine is as shown. II, H

0

0

indicates that the (+) -(2R,2'R)threo isomer is involval

Phendimotrazirie Tartrale

Sibutramine. Sibutramine (Meridia) is said to be an uptake inhibitor of NE and 5-HT. These mechanisms fit its structure. It is reportedly an antidepressant and an anorexiant

drug. This mechanism implies that activation of all presynaptic and postsynaplic receptors in NE and 5-HT systems is possible. The data are not completely clear, hut studies to date indicate that the receptors principally involved are a1. and

A

Methytphenldate Hydrochtoride

Il

Pemoline. The unique structure ol pemoline. 5-phcnyl-45H)-oxazolone (Cyleru), is shown below,

.CH3

Pemoline

The compound is described as having an overall

the CNS like that of methylphenidatc. Pemolinc to 4 weeks of administration, however, to take effect partial explanation for the delayed effect may be that to of the actions of the agent, as observed in rats, is to inctocs

the rate of synthesis of DA. Sibutramine

Methylphenidate

Hydrochloride,

ANTIDEPRESSANTS LiSP.

Because

methylphenidate (Ritalin) has two asymmetric centers, there

are four possible isomers. The tlireo racemate is the mar-

Oiddase Inhibitors (MAOIs) Antidepressant therapy usually implies therapy direct:J against major depressive disorders of the unipolar

Chaptor 15 • Central Nen'au.c System Stimulants

is centered around three groups of chemical agents: the

515

MAOIs. the monoamine reuptake inhibitors, and autorecepor desensitizers and antagonists. Electroshock therapy is

inhibition was almost always regarded as irreversible. From the beginning, however, it was known that it was possible to have agents that act exclusively by competitive enzyme

another option. The highest cure or remission rate

inhibition. For example. it has long been known that the

is

achieved with electroshock therapy. In some patients. especially those who are suicidal, this may be the preferred therapy. MAOIs and monoamine reuptake inhibitors have about the same response rate (—60 to 70%). In the United States. the latter group is usually chosen over MAOls for antidepres-

hannala alkaloids hurmine and harmaline act as CNS stimu-

lants by competitive inhibition of MAO. Reversible (competitive) inhibitors selective for each of the two major MAO subtypes (A and B) are reportedly forthcoming.

HO

Ill -

sant therapy.

A severe problem associated with the MAOIs that has a major factor in relegating them to second-line drug status is that the original compounds inhibit liver MAOs irreversibly in addition to brain MAOs. thereby allowing dietary pressor amines that normally would be inactivated tocscrt their effects systemically. A number of severe hyperwnsive responses, some fatal, have followed ingestion of (seds high in pressor amines. It was hoped that the developsteal of agents such as selcgiline that presumably spare liver MAO might solve this problem. The approach of using MAO selectivity did solve the hypertensive problem, but the cornwas not an antidepressant (it is useful in Parkinson's disease). Another approach using a reversible MAOI has yielded antideprnssants that lacked the hypertensive

effect. Another prominent side effect of MAOIs aorthostatic hypotension. said to arise from a block of NE released in the periphery. Actually, one MAOI, pargyline, sac used clinically for its hypotensive action. Finally, sonic the first compounds produced serious hepatotoxicity. Compounds available today reportedly are safer in this recard but suffer the stigma of association with the older corn-

The history of MAOI development illustrates the role of Isoniazid is an effective antitubereular agent hut a very polar compound. To gain better penetration into the ,tfvcobac:eriu,n tuberculosis organism, a more hydrophobic compound, isoniazid substituted with an isopropyl group on de basic nitrogen (iproniazid). was designed and synthesord. It was introduced into clinical practice as an effective arlitubercular agent. CNS stimulation was noted, however.

and the drug was withdrawn. Later, it was determined in caperimentail animats and in vitro experiments with a purified MAO that MAO inhibition, resulting in higher synaptic kwls of NE and 5-HT. could account for the CNS effecis. compound was then reintroduced into therapy as an nlidepressant agent. It stimulated an intense interest in hydnaiunes and hydrazides as anridepressants and inaugurated effective drug treatment of depression.22 It continued to be

0

C

Mociobemide

Moclohernide has received considerable attention abroad.

A reversible inhibitor of MAO-A, it is considered an effective antidepressant and permits metabolism of dietary myramine.2a Metabolites of the drug are implicated in the activity.

Reversible inhibitors of MAO-A (RIMAs) reportedly are antidepre.s.sant without producing hypertensive crises. Reversible inhibitors of MAO-B have also been studied. Pres-

ently, selective MAO-B inhibition has failed to correlate positively with antidepressant activity; selegilinc. however. has value in treating Parkinson's disease. The clinically useful MAOI antidepressunts are nonselective between inhibiting metabolism of NE and 5-HT. Agents selective for a MAO that degrades 5-HT have been under study for some time. The structures of phenelzine and tnanyl-

cyprominc are given in Table 15-4

Pheneizine Sulfate, (iSP. Phenelzine sulfate. 2-(phenyleihyl)hydrazine sulfate (Nardil). is an effective antidepressant agent. A mechanism-based inactivator. it irreversibly inactivates the enzyme or its cofactor. presumably after oxidation to the diazine, which can then break up into molecular nitrogen, a hydrogen atom, and a phenethyl free radical. The latter would be the active species in irreversible inhibi-

Tranykypromine Sulfate, (iSP.

Tranylcyprominc sul-

fate. (± )-rran.c.2-phenylcyclopropylamine sulfate (Parnate), was synthesized to be an amphetamine analogue (visu-

alize the a-methyl of amphetamine condensed onto the 13carbon It does have some amphetamine-like properties, which may be why it has more immediate CNS stimulant effects than agents that act by MAO inhibition alone. For MAO inhibition, there may be two components to thc

ned in therapy for several years but eventually was withyawn because of hepatotoxicity.

The present clinically useful irreversible inactivators can reconsidered mechanism-based inhibitors of MAO.23 They

re converted by MAO to agents that inhibit the enzyme. flay can form reactants that bond covalently with the eninc or its cofactor. A consequence of irreversible inactivais that the action of the agents may continue for up to 2 seeks after administration is discontinued. Consequently, sny drugs degraded by MAO or drugs that elevate levels if MAO substrates cannot be administered during that time. For a long time, because the agents that opened the field

i'd then dominated it were irreversible inactivator. MAO

TABLE 15-4

Monoamine Oxldase InhIbitors

Generic Name Proprietary Name

Sfructure

Phanoizine

H2S04

NatCid Tranyscypromirre nultale, USP Pamare

rj—CH_CH_-NH

516

IVi/Min and GistoisI

s

ie.sll,susk a! Orc,'a,,is Medicinal tim! Plwrn,aeeuiical

action of this agent. One is thought to arise because tranylcy-

prominc has structural feattires (the basic iiitrogeii and the quasi-IT character of the a- and

carbon

atoms) that approximate the transition state in a route of nietubolism of $-arylamines.27 As a- and $-hydrogen atoms are removed from the normal substrate of the enzyme. the quasi-ar character develops over the a.f3-carhon systeni. Duplication of the transition slate permits extremely strong, but reversible, attachment to the enzyme. Additionally, Iranylcypromine is a mechanism-based inactivator. It is metabo-

lized by MAO, with one electron of the nitrogen pair lost to liavin. This, in turn. produce.s homolytic fission of a carbon—carbon bond of cyclopropune. with one electron from the fission pairing with the remaining lone nitrogen electron to generate an imine (protonaled) and with the other residing on a methylene carbon. Thus, a free radical is formed that

reacts to form a covalent bond with the enzyme or with reduced tiavin to inactivate the enzyme.25

Monoamine Reuptake Inhibitors Originally, the monoamine reuptake inhibitors were a group of closely related agents. the tricyclic antidepressants. but

now they are quite diverse chemically. Almost all of the agents block neuronal reuptake of NE or 5-HI or both (i.e.. are selective). Reuptake inhibition by these agents is at the level of the respective monoamine transporter via competitive inhibition of binding of the monoamine to the substrate-binding compartment. Probably the same site on the protein is involved

('ls',nisirv

the substrate-binding compartment of the transporter. The overall concept of a system with addcd structural bulk, usually an aryl group, appears to be applicable to many newer compounds—selective serotonin reuptake inhibitors (SSRIs). selective norepincphrine reuptake inhibitors (SNERIs)—that do not have a tricyclic grouping. The TCAs arc structurally related to each other and, consequently, possess related biological properties that can summarized as characteristic of the group. The dimethyla. mint, compounds tend to he sedative, whereas the mono' methyl relatives tend to be stirnulatory. The dimethyl compounds tend toward higher 5-HT to NE rcuptake block ratios: in the monomethyl compounds. the proportion of NE uptakc

block tends to be higher and in some cases is selective NE reuptake. The compounds have anticholinergic properties, usually higher in the dimethylamino compounds. When treatment is begun with a dimethyl compound. a sig. nificant accumulation of the monomethyl compound desclops as N-demethylation proceeds. The TCAs are extremely lipophilic and, accordingly. sen highly tissue bound outside the CNS. Since they have anticholinergic and noradrenergic effects, both central and jv. ripheral side eliects are olien unpleasant and sometimes dam gerous. In overdose, the combination of efl'ects. as well as a quinidine-like cardiac depressant effect, can be lethal. Os. erdose is complicated because the agents are so highly pro-

tein bound that dialysis is ineffective.

for inhibitor and monoamine, but this has not yet been

PRODUCTS

proved. The mechanism of reuptake by monoamine trans-

Imipramine Hydrochloride. USP.

porters has been reviewed.39

The net effect of the drug is to increase the level of the monoamine in the synapse. Sustained high synaptic levels of 5-HI. NE, or both appear to be the basis for the antideprcs.sant effect of these agents. There is a lime lag of 2 or more weeks before antidepressant action develops. It is conSHTIA receptors and (in sidered that (in the case of the case of NE) a2 receptors undergo desensitization and transmitter release is maintained. Of course activation of postsynaptic receptors and sustained transmission is the ulti-

mate result of sustained synaptic levels of neurotransmitter.°

Tricydic Antidepressants The SARs for the TCAs are compiled in detail in the eighth edition of this text.32 The interested reader is referred to this compilation. In summary, there is a large, bulky group

encompassing two aromatic rings, preferably held in a skewed arrangement by a third central ring, and a three- or. sometimes, two-atom chain to an aliphatic amino group that is monomethyl- or dimethyl-substituted. The features can be

visualized by consulting the structures of imipramine and desiprumine as examples. The overall arrangement has features that approximate a fully extended Irons conformation of the $-arylamines. To relate these features to the mechanisna of action. reuptake block, visualize that the basic ar-

rangement is the same as that found in the plus an extra aryl bulky group that enhances affinity for

lmipramine chloride. 5-13-(dimethylamino)propyl I-It), II -dihydro-illdibenzlbjlazepine monohydrochlonde (Fofranil). is the lead compound of the TCAs. It is also a close relative of the antipsychotic phenothia-zines (replace the 10—Il bridge with sulfur, and the compound is the antipsychotic agent pram zinc). It has weaker D2 postsynaptic blocking activity thaa

proma/ine and mainly affects amines (5-HI. NE. and DAt via the transporters. As is typical of dimethylamino compounds. anticholinergic and sedative (central H5 blockcl fects tend to he marked. The compound per se has a tendency

toward a high 5-HT-to-NE uptake block ratio and can be called a serotonin transport inhibitor (SERII). Mcu. bolic inactivation proceeds mainly by oxidative hydrox>la.

tion in the 2 position, followed by conjugation with ronic acid of the conjugate. Urinary excretion predonilnalo

(about 75%), but sotne biliary excretion (up to 25'if) occur, probably because of the large nonpolar grouping. Os

dative hydroxylation is not as rapid or complete as that ii the more nucleophilic ring phenothiazine antipsyclrotic'. consequently, appreciable N-demethylation occurs. ssilb buildup of norimipranline (or desimipramine). The dcmcthylutcd mctabolitc is less anticholinergic. sedative, and more stimulatory and is a SNERI.3' quently. a patient treated with imipramine has two cm pounds that contribute to activity. Overall, the effect selective 5-HI versus NE reuptake. The activity of des-norilnipramine is terminated by 2-hydroxylation. by conjugation and excretion. A second N-denrethylarits

Chapter 15 • Central

occur. which in turn is followed by 2-hydroxylation.

line. Nortriptyline is a SNERI3: the composite action of drug and metabolite is nonselective.

and excretion. 9

517

Svstun

1

Nortriptyline Hydrochloride, USP.

Pertinent biologi-

cal and chemical properties for nortriptyline. 3-(I0.l 1-diN 6

/CH3

4

HCI R

Imipranitne Desipramine

R

= CH3

R

H

hydro-5H.dibenz.o(a.djcyclohepten-5-ylideneN-methyl- I propanantine hydrochloride. 5-(3-methyl-aminopropylidene)- 10.11 -hydro-511-dibenzola,dlcycloheptcne hydrochloride (Aventyl. Pamelor). are given above in the discus-

sion of amitriptyline. Metabolic inactivation and elimination are like those of amitriptyline. Nortriptyline is a selective NE transporter (NET) inhibitor.3'

Cesipramine Hydrochloride, USP. The structure and properties of desipramine hydrochloride. 10,11 -dihydro-N-methyl-5H-dibenz(bJlazepinc-5.propanamine monohydrochloride. 5-(3-methylaminopropyl)- 10,11 -dihydro511.dibcnzlbflazepine hydrochloride (Norpramin. Perto-

/CH3 HO

irane). are discussed under the heading. Imiprarnine. above.

Among tricyclics. desipramine would be considered when few unticholinergic effects or a low level of sedation are

R Arndriptyhne. Noririptyline

R = CH3 P=H

important. It is a SNERI.31

Hydrochloride. Clomipraminc (Anaarni) is tip to 50 times as potent as imipramine in some This does not imply clinical superiority, but it might be informativc about tricyclic and, possibly. other cuptake inhibitors. The chloro replacing the H substitueni could increase potency by increasing distribution to the Clomipramine

is unlikely that this would give the potency

UNS. but it

magnitude seen. It might be conjectured that a H bond beseen the protonated amino group (as in vivo) and the Unelectrons of the chloro substituent might stabilize a $aiylamine-like shape and give more efficient competition (or the transporter. The drug is an antidepressant. It is used a obsessive-compulsive disorder, an anxiety disorder that

Protriptyline Hydrochloride, USP.

Protriptyline hydrochloride. N-methyl-5H-dibenzo[a,d]cyclohcptenc-5-propylamine hydrochloride. 5-(3-methylaminopropyl).5H-dibenzofa.dlcycloheptene hydrochloride (Vivactil). like the other compounds under consideration, is an effective antidepressant. The basis for its chemical naming can be seen by consulting the naming and the structure of imipramine. Protriptyline is a structural isomer of noririptyline. Inactivation can be expected to involve the relatively localized double bond. Because it is a monomethyl compound, its sedative potential is low.

may have an element of depression.

CH2—CH2—CH2—N CH3 Protriplyfine

Trimipramine Maleate.

CH3

Clornipramirie

A.rnitrlptyline

Hydrochloride,

USP.

Amitriptyline. 3-

10.1

I

For details of chemical no-

menclature, consult the description of imnipramine. Replace-

.propanamine hydrochloride. 5-(3-dimethyl-

10,11 -dihydro-5H-dibenzola.djcyclohepate hydrochloride (Elavil). is one of the most anticholinerand sedative of the TCAs. Because it lacks the ring dccion-enriching nitrogen atom of imipramine, metabolic inmainly proceeds not at the analogous 2 position stat the benzylic 10 position (i.e.. toluene-like metabolism relominatcs). Because of the 5-exocyclic double bond. EZ•hydroxy isomers arc produced by oxidation metaboa Conjugation produces excretable metabolites. As is of the dimethyl compounds. N-demethylation occurs, is produced, which has a less anticholinerIeee. sedative, and more stimulant action than umitripty-

ment of hydrogen with an a-methyl substituent produces a chirai carbon, and trimipramine (Surmontil) is used as the racemic mixture. Biological properties reportedly resemble those of imipramine.

QQQ I

i

C

CH2 — N

I

CH3

CH3 Trimipramine

Doxepin Hydrochloride, USP.

Doxepin, 3-dibenz-

Ib,el-oxepin- II (6H)ylidine-N.N-dimethyl- I -propanamine

518

Wilso,, and (;isi'old c Tes:!;ook

of Organic Medici,,aI and Pharmaceutical CI,en,i.cfr.'

hydrochloride. N.N-dimethyl-3-(dihenzlh.ejoxepin- II (6H)ylidene)propylaminc (Sinequan. Adapin). is an oxa congener of arnitriptyline. as can be seen from its structure. The oxygen is interestingly placed und should influence oxidative metabolism as well as postsynaplic and presynap-

tic binding affinities. The (Z) isomer is the more active, although the drug is marketed as the mixture of isomers. The drug overall isa NE and 5-HI reupiake blocker with significant anticholinergic and sedative properties. It can be arnicipated that the nor- or des- metabolite will contribute to the

overall activity pattern. 7

4

8

10

liii

CH3 I

HC—CH,—CH,—N

\

HCI

abolishes the center ring, and one ring is moved forward from the tricyclic "all-in-a-row" arrangement.) The net effect is that the fl-arylamine-like grouping is present. as in the tricyclics. and the compounds can compete Inn the substrate-binding site of the serotonin transporter protein

(SERT). As in the tricyclics, the extra aryl group can add extra affinity and give favorable competition with the sub. stratc. serotonin. Many of the dimethylamino tricyclics are, in fact, SSRk

Since they are extensively N-demethylated in vivo to compounds. which are usually SNERIs. however, the effect is not selective. Breaking up the tricyclic system breaks up an anticholinergic pharmacophoric group and gives compounds with diminished anticholinergic efiecis Overall, this diminishes unpleasant CNS effects and 1n creases cardiovascular safety. Instead, side effects related It serotonin predominate.

CH3

Fluoxetine.

protonaled in vi,n In Iluoxetine the protonated amino group can H-bond to the ether oxygen

Donepin Hydrochloride

Maprotiline Hydrochloride, USP.

Maprotiline hydrochloride. N-methyl-9. tO-ethanoanthracene-9( I OH)-propanamine hydrochloride (Ludiomil), is sometimes described as a tetracyclic rather than a tricyclic antidepressant. The description is chemically accurate, but the compound, nonetheless. conforms to the overall TCA pharmacophore. It is

electrons, which can generate the gnwp. with the other aryl serving as the characteristic "extra" The S isomer is much more selective for SERT than Icr NET. The major metabolite is the N-dernethyl cornponrst which is as potent as the parent and more selective (SERT versus NET).

a

Therapy for 2 or more weeks is required for the aittidepre' sant effect. Somatodendritic 5HTIA nutoreceptor dcsenciti.

an

a

ethylene-bridged central ring. The compound is not

strongly anticholincrgic and has stimulant properties. It can have effects on the cardiovascular system. It is a

zation with chronic exposure to high levels of 5-HI is Ik accepted explanation for the delayed effect for this and odar

serotonin reuptake inhibitors. To illustrate a difference between selectivity for a SF.R1 and a NET, if the pare: substituent is moved to the aid position (and is less hydrophobic, typically), a NET is tamed. This and other SERTs have anxiolytic activity. Oix of several possible mechanisms would be agonism of 5HT receptors. diminishing synaptic 5-HT. Presumably. sytlaplh

levels of 5-HT might be high in an anxious state. Maprotiline Hydrochloride

Amoxaplne.

Consideration of the structure of arnoxapinc. 2-chloro- Ii -( I -piperaiinyl)dibenz-Ib.J1 II ,4loxazepine (Asendin). reinforces the fact that many antidepressants are very closely related to antipsychoties. Indeed, some, including amoxapine. have significant effects at receptors. The N-methyl-substituted relative of arnoxapine is the antipsymetabolite of chotic loxapine (Loxitane). The umoxapine is reportedly active as an antidepressant and as a Da receptor blocker.

0 NHCH3 Fluoxetine

Paroxetine. In the structure of paroxetine amino group. protonated in vivo could U-bond with —CH2—O— unshared electrons. A

strucsr:

with an extra aryl group results. The compound is a icr highly selective SERT. As expected. it is an effective pressant and anxiolytic.

Anioxapino

Selective Serotonin Reuptake Inhibitors Structurally, the SSRIs differ from the tricyclics. in that the tricyclic system has been taken apart in the center. (This

Paroneline

Chapter 15 • Central Nenvu.c System Sti,nt,lanzs Sertraline.

Inspection of seriraline (Zoloft) (lS.4S) re-

the pharnmcophore for SERT inhibition. The Cl sub-

also predict tropism for a 5-HI system. The depicted stereochemistry is important for activity. H

Most ol the activity of rehosetine resides Reboxetine. in the SS isomer (The marketed compound is RR and SS. It is claimed to he superior to Iluoxetinc in severe depression. It is marketed in Europe. At least three tricyclic compounds.

nortriptyline. and the technically tetracyclic

NHCH3

•HCI

i-i

519

maprotiline are SNERIs. They. of course. have typical characteristic TCA side effects hut lower anticholinergic and antihistaminic (sedative) effects than dimethyl compounds. SNERIs are clinically effective antidepressants. H

Sertratne

The E isomer of Iluvoxamine (Luvox) shown) can fold after protonation to the hydrophobic group is aliphatic. grouping. Here the

Reboxetine

Fluvoxamine

Citalopram (Celexa) is a racemic mixture is very SERT selective. The N-monodemethylatcd corn-

is slightly less potent hut is as selective. The aryl 'ubstiluents are important for activity. The ether function is immportant and probably interacts with the protonated amino

to give a suitable shape for SERT binding.

It would be expected that in the case of SNERIs. a5 presynaptic receptors would be desensitized. after which sustained NE transmission would be via one or more postsynaptic icreceptors are possibilities. ceptors; a1. and

Newer (Nontricyclic) Nonselective 5-HI and NE Reuptaka Inhibitors Presently. one such compound is clinically used in the United States.

The stnlcture and activity of venlafaxine Venlafaxine. (Effexor) are in accord with the general SARs for the group. As expected, it is an effective antidepressant. CH1

/N CH3

Citalopram

Selective Noreplnepbrlne Reuptake the discussion of fluoxetine opened the subject of SNERIs. flat is. movement of a porn substituent of Iluoxetine (and to an org/u, position produces a SNERI.

cl-Is

Selective Serotoninergic Reuptake Inhibitors and Antagonists The SSRIs and 5HTSA antagonists are represented by trazodone (Desyrel) and nefazodone (Serione).

\J Nisoxetine

Nisoxetine is a SNERI and is an antidepressant. Most resides in the

isomer.

The structures of these two compounds derive from those al the lluorobutyrophcnone antipsychotics. They have arylaminc-like structures that permit binding to the SERT

520

Wi/am and Gisiohl'.s

o Nefazodone

and inhibit 5-HT reuptake. In these compounds. the additional hydrophobic substituent can be viewed as being atgroup. Additached to the nitrogen of the tionally. they are antagonists. That antagonism may or may not afford antipsychotic eftéctiveness is discussed under antipsychotics. 5HT2A antagonists appear to have anti-

depressant and anxiolytic activities. They may act, at least in part, by enhancing SI-ITIA activities." Also, some of the effects may be mediated through agonism (perhaps 5-HT-acting antidepressams.) Some of the generally so side effects of SSRIs arc considered to he mediated through

Miscellaneous Antidepressants Bupropion.

The mechanism of action of

(Wellbutrin) is considered complex and reportedly involse' a block of DA reuptake via the dopamine transporter (DAT), hut the overall antidepressant action is noradrenergic. A tabolite that contributes to the overall action and its formation can be easily rationalized.

(,}

SHT2A receptors. so a 5HT2A blocker would reduce them.33 The two compounds yield the same compound on N-dealkyl-

ation. It is a serotonin reuptake inhibitor.

Agonists and Partial Agonists

Buproplon CI

Buspirone. The initial compound in this series. buspirone (BuSpar). has anxiolytic and antidepressant activities and is a partial 51-ITIA agonist. Its anxiolytic activity is reportedly due to its ability to diminish 5-HT release (via 5HTIA agonism). High short-term synaptic levels of 5-HT are characteristic of anxiety. Also, since it isa partial agonist. it can stimulate postsynaptic receptors when 5-HT levels are low in the synapse. as is the case in depression. A number of other spirones are in development as anxiolytics and antidepressants.3'

HO N H

•CH3 Metabolito

MISCELLANEOUS CNS-AcTING DRUGS Buspirone

Antagonists Mirtazapine.

Mirtazapine (Renicron) was recently introduced for clinical use in the United States; its parent mianse,-in (pyridyl N replaced with C-H) was long known to be an antidepressant. It is reported to be laster acting and more potent than certain SSRIs. The mode of action gives increased NE release via a2-NE receptor antagonism and increased 5-HI release via antagonism of NE a2 heteroreceptors located on serotoninergic neurons.33'

This section deals with a collection of drugs that do easily under other topic headings in this chapter or the ter on CNS depressants. All of the drugs are drugs of abue and could be organized under that heading. The fl-arylamino hallucinogens arose because of in the naturally occurring hallucinogens psilocin and mesci line and in modifying the amphetamines, which were popular drugs at the time. Lysergic acid diethylamide was dentally discovered during research on ergot alkaloids. flof scientific interest because it serves as one model forchincal psychosis. Phencyclidine is scientifically intemstingk cause it gives information about the ionotropic N-methyl-iasparlate glutamic acid receptor. and its CNS effects as a model for schizophrenia. Cocaine usa CNS stimulant is a pernicious drug of Research on why it is so strongly addictive and on duu measures that might mitigate its effects has been the past two decades.

.i'-Tetrahydrocannabinol and its relatives were

Mirtazapine

for many years to determine the SAks. The field was gni stimulus with the discovery of the endogenous cannahing_ receptors. Presently, the endogenous cannahinoid sysicrn under investigation.

Chapter IS N Centra! Nervous Svsfrn, Ssi,mdan:.c

1/3.Arylamlno Halluclnogens

521

CH3O

A property of the I f3-arylamino hallueinngcns is alteration of the perception of stimuli. Reality is distorted, and the user may undergo depersonalization. Literally. the effects are those of a psychosis. Additionally, the drugs can produce

CM2 — CH2 — NH2

CH3O

CH3O

anxiety, fear, panic. frank hallucinations, and additional

Mescaline

symptoms that may he found in a psychosis. Accordingly. hey are classed as hallucinogens and psychotomimetics. This group can be subgrouped into those that possess an mdolethylamine moiety, those that possess a phenylethylani-

ne moiety, and those with both. In the lust group. there is a structural resemblance to the central neurotransmitter 5I-IT, and in the second, there is a structural resemblance to NE and DA. This resemblance is suggestive, and there may he sonic selectivity of effects on the respective transmitter systems. With structures of the complexity found in many of these agents, however, a given structure may possibly affect not just the closest structurally related neurotransmit-

CH3O

CH2 CHNH2

CM3

OCH3

-Dimethoxy4-metphenyq-2-amlne (DOM. SIP)

tsr systems but other systems as well. Thus, a phenethylam-

ins system could affect not only NE and DA systems but also 54-IT systems, and an indolethylamine system could affect not only 5.HT but also NE and DA systems.

CM3

3.4-Methytenedioxyamphetamlna (MDA)

INDOLETHYLAMINES CH2CHNHCH3

Dimethylt,yptamine. Dimethyltryptamine is a very weak hallucinogen, active only by inhalation or injection.

CM3

with a short duration of action. It possesses pronounced symçsihomimetic (NE) side effects.

Psilocybln

and Psilocin.

Psilocybin is the phosphoric

acid ester of psilocin and appears to be converted to psilocin as the active species in vivo. It occurs in a mushroom. Psiloi)he montana. Both drugs are active orally, with a short suration of action.

Synthetic a-methyl-substituted relatives have a much lunger duration of action and enhanced oral potency.35 This suggests that psilocin is metabolized by MAOs. R

DMDA (ecstasy)

The presence of methoxyl or dioxymethylene (methylenedioxy) substituents on a 2-phenethylamine system is a characteristic olmany psychotomimclic compounds and strongly suggests DA involvement. AGENT POSSESSING BOTH AN INDOLETHYLAMINE AND A PHENYLETHYLAMINE MOIETY

(+).Lyserglc Acid Diethylamide.

Both an indolethylamine group and a phenylethylamine group can be seen in the structure of the extraordinarily potent hallucinogen lysergic acid diethylamide (LSD. The stereochemistry is ex-

ceedingly important. Chirality. as shown, must be mainCH3 H Dimethyllryptamine Psuiocybin

Psilocin

=H Ft4 = OPO(OH);.. Ft5 = K Ft,1 = OH, Ft5 = H Ft4 =

2•PHENYLETHYLAMINES

Mescaline. 3,4.5.trimethoxyphenethylamuc. is a much-studied hallucinogen with many complex efItcis on the CNS. It occurs in the peyote cactus. The oral required for its hallucinogenic effects is very high. as much as 5(X) mg of the sulfate salt. The low oral potency purbably results from facile metabolism by MAO. a-Methyllion increases CNS activity. Synthetic a-methyl-substituted relatives are more potent.35

tained or activity is lost; likewise, the location of the double bond, as shown, is required.37 Experimentally. LSD has marked effects on seroloninergic and dopaminergic neurons. The bases for all of its complex CNS actions are not completely understood, however. Recently. its actions have been suggested as being more typical of schizophrenic psychotic reactions than the model based on amphetamine. For more on this. see the discussion of atypical antipsychotics (Chapter 14).

0 C2H5

.-'ie

N H 2

5

Ar

The drugs DOM. MDA. and

DMDA (ecstasy) are extremely potent. dangerous drugs of Lysergic Acid Dreihylamido

522

Ttxd,ook of

Wilson wid

Medieinal and Phannact',uiral C'h,',,,iqrv

Depressant-Inti

Dissoclalive Agents

or

Phencyclidine.

Phencyclidine (PCP) was ititroduced as a dissociative anesthetic for animals. Its close structural ida-

live ketaminc is still so used and may he used in humans (Chapter 14). In humans. PCP produces a sense of intoxucalion, hallucinogenic experiences not unlike those produced by the anticholinergic hallucinogens. and often amnesia.

The drug affects many systems. including those of DA. and 5-HI. It has been proposed that PCP (and certain other psychotominnetics) produces a unique pattern of activation of ventral tegumenial area dopaminergic neurons. II blocks glutaminergic N-methyl-o-aspartate receptors. " This action is the basis for many of its CNS effects. PCP itself appears to he the active agent. The psychotic state

CH3

produced by this drug is also cited as a better model than amphetamine psychosis for the psychotic state of

CH3 10

schizophrenia.30

—

Phencychdine Hydrochloride

Cocaine. Cocaine as a euphoriant—slimulant. psychotomimetic. and drug of abuse could as well be discussed with amphetamine and methamphetamine. with which it shares many biological properties. At low doses. ii produces feelings of well-being, decreased faligue. and increased alertness. Cocaine tends to produce compulsive drug-seeking behavior. and a full-blown toxic psychosis may emerge. Many of these effects appear to be related to the effects of increased Nccss

(D1 and

receptors are pertinent). Cocaine is a potent DA

reuptake blocker, acting by competitive inhibition of the DAT. A phenethylamine moiety with added steric hulk may suffice for this action. An interaction between a hydrogen atom on the nitrogen of the proconated form of cocaine and an oxygen of the benzoyl ester group, or alternatively, an interaction between the unshared electron pair of the freebase nitrogen and the carhonyl of the heni,oyl ester group. could approximate this moiety.

o

0CH3

There are twir

conventions for numbering THC: that arising from chemistry produces J'-Tl-IC. and that based on the diks zopyran system results in a J"-THC designation. The noid convention is used here.

TetrahyQrocarlriabinol

TI-IC is a depressant with apparent stimulant sensarior, arising from depression of higher centers. Many effects. re putedly subjectively construed as pleasant. are evident low doses. The interested reader may consult a phararaurl ogy text for a detailed account. At higher doses. psychotorni metic actions, including dysphoria. hallucinations. and pin noiu, can be marked. Structural features associated with activity among cannabis-derived compounds have been c

Notably. the phenolic OH is required for Certain SAks (especially separation of potency bctwecncn antiomers) for cannahi noids suggested action at receptors.' Two receptors fur THC have been discovered. The relesan' receptor for CNS actions is C13,,44 occurs in immure tissues. The first natural ligand k,u,td for the receptor is the amide derivative of arachidonic acid, anandamide.45 Ot}ei natural cannahinoids arc urachidonic acid 2—glycerol oar and 2-arachidonyl glycerol ether." The endogenous hinoid system appears to function usa retrograde messenge system at both stimulatorv synapses and depressant syr apses. 'The synaptic transmnirter causes ses of endocannahinoids that are then transported to receptors located presynaptically where they fine-tune excitatory and inhibitory neurons.47 Because CB, rcceg turs appear to be present in all brain areas and atlect excitatory and inhibitory systems, the prospect selective cannabinoid drugs acting at receptors is not good. Designing drugs to affect the transporter is conciJ ered the most promising research route. Endocannahinoids. as regulated by leptin. are also in maintaining food intake and in other behaviors.°'51 REFERENCES I. Jartioe. C. H.. Porler. L. A.. and Buckler. R. T.: J. Mcd. Cliro 729. 1965. 2. Pcllmar. 'F. C., and WitMin. W. A Science 197:912. 1977,

A

Cocaine

Considerable research on drugs affecting the DAT has been published in recent years. A review of pharmacotherapeulic agents br cocaine abuse is available.4'

3. Fredholm. B. B.. et iii.: t'har,nacol. Res .51113. 1999. 4. Daly. J. W.: J. Med. Cl,ei,r. 25.t97. 9112. 5, SI.. and J. It Anna, Rep Mcd. Chcm. 111:1, Is' 1, Snydrr. S. It.. em al. Proc. Null. Acad Sri It. S A. 'i 7. Tuckei'. A. L.. and Limideti. J.: Re, 27:62. 8. liriun. M. D.: Annu. Rep. Mcd. Cltcm. 211:295. 993. 9 t)cN,nno. M. P.: Anna. Rep. Med. Clicin .33:111. 9911 Ill Arn,ntd. M 1.: ii,cl:iholi.,ii ,if catle,t,e. In Dews. P Caffeine. From Recen, Re,earch. Ncw York. Verlag. 9114. p. 3.

Chapter IS • Central Nen'ous Sy.s rc'nt

1

2

I), 4

I))

IIa)ionJ. 3. C. 0.. und Blundell. 1. 0.: Prop. Drug Res. 54:25. 20(X).

Filler. K W.: Ann. N. Y. Acad. Sd. 305:147, 1978. liatser, 3. A.: Ann. N.Y. Acad. Sei.305:289, 1978. Groppefli. A.. and Cosia. E.: Life Sri. 8:635, 1969. Clineschtnidl, 8. V., et ul.: Ann. N. Y, Aced. Sci. 305:222, 1987. l)voniik. U.. and Schilling, Cr.: 3. Med. Chrm. 8:466. (965. Wejs,i, I.. and Dudas, A.: Monaish. Chem. 91:840, 1960.

lUte, 0.: 3. Mcd. Chent. (2:266, (969. eta).: .1. Pharmucol. Exp. TIter. 241:152. (987. 20. ('crc), 3. M.. and Dayton. P. (3.: Mcihylphenidate. In Usdin. 13.. and Fmrest. I. S. teds.). Psycholherapcuiic Drugs, pail II. New York. Marcel Dekker. (977, p. 287. II. Srittsa.s. N. R., ci iii.: 3. Pharinacol. Eap. 'liter. 241:300, (9(17. 12. Whitclock, 0. V. led.): Ann. N. V. Acad. Sci., 8(1:1881—188), (959. 23. Richards. L. E.. and Burger. A.: Frog. Drug Rcs.30:205, (986. 23. Strupc,.ewski. 3. 0.. Ellis. D. B.. and Allen, R. C.: Annu. Rep. Med. ('hem. 26:297, 1991. 27. Green. A. L: Biochcm. l'hamiacol. (3:249, (964. 20. Burger. A.: J. Med. Pharm. Otem. 4:571. 1961. 17. Kelleau, B., and Mor.tn, 3. F.: J. Am. Chem. Soc. 82:5752. (960. 27. Bclleait, B.. and Moran, 3. F.: 3. Mcd. Phann. Client. 5:215. (962. 3) Silvennan. R, 8.: 3. Rio). Chem. 258:14766, 1983. 70. Rudnick, 0., and Clark. 3.: ISiochim. Biophys. Aria 1144:249. 1993. 'I. Ohvicr, B.: Frog. Drug Rex. 54:59. 2(88). IS. Shaffi'ee. 9. Putnck. K

11

Daniels, T. C., and Jorgensen. E. C.: Cenlral nervous system slimulanis.

In Doerge, R. F. led.). Wilson and Giavold's Textbook of Organic Medicinal and Pliarniaceutical Chemistry. lllh ed. Philadelphia, J. B. Lippiucoti. 1982. p. 383. 73. Erred, 0. A.. and Hamsoii, B. 1..: Aitnu. Rep. Mcii, Chein.34:l. 1999. 74. Olivier, B., ci al.: Prop. Drug Res. 52:103. 999. 73. Murphree. H. B.. eta).: Clin. Phurmacol. Tttcr. 2:722. 1961. 70. Shulgin. A. T.: Naiutre 201:120. 1964.

Sin)). A.. and Holmann. A.: HeIr. 0dm. Aria 38:42). 1955. 7) lowers, M. B.. Bannctn, M. 3., and Hoffman, 0. J.. Jr.: Psycltopliarnia. eulogy 93:133. 1987.

523

39. Foster. A. C.. and Fogg. 0. 0.: Nature 329:395. 1987. 40. Rowley. M.. Bristow. L. 3., aiid Hutson. P. H.: 3. Med. Chetn 44:477, 2(8)1.

41. Carroll. F. I.. Howell. L. L,and Kuhov. M. J.: I. Med. Cbcm. 42:2721. 20(X).

42, Edery, H.. ci al.: Ann. N. Y. Arad. Sci. 191:40. 1971. 43. Hol)istcr. I.. 13.. Gillespie. II. K.. and Srehnik. M.: Psydltophannacology 92:505. 1987. .14. Matsuda. L. A.. ci al.: Nature 346:561. (99(3. 45. Davannc. W. A.. ci a).: Science 258:1946, (992. 46. Mcchou(nm. R., ci al.: Proc. Nail. Acad. Sc), U.S.A. 98:3602. 2(101. 47. Egeriovu. M.. ci al.: Proc. R.Soc. London B 265:21)8. (998. 48. Wilson, R. I. and Nicoll. R. A.: Nature 4(0:588, 218(1. 49. Ohn-Shosaku. T.. Maejqma. 1.. and Kano. N.: Neuron 29:729, 2(8)1. 50. Krciizer, A. C.. and Rcgehr. W. 0.: Neuron 29:7(7, 2(101. 5). Chrisde. M. 3.. and Vaughn. C. W.: Nature 4(0:527. 2(8)1. 52. DiMar,.o, V.. eta).: Nature 410:822, 2001. 53. Mcchoulam, K., and Fride. 0.: Nature 4(0:763, 200).

SELECTED READING Currol. F. I.. Howell, F. I., and Kuliar. M. 3.: l'harnxacoihcrupies (or treatment of cocaine abuse: Preclinical aspects. 3. Mcd. ('hem. 42:2721. 2000.

Frcdholtn. B. 8.. Battig K.. Holiiieit, 3.. et al.: Actions of caffeine in the brain with special reference to (actors thitt contribute to its widespread use. Pttartnacol. Rev. 51:83. 1999. Hulford. 3. C. (1.. and Blundell. 3. 11.: Pharmacology oFappelile suppression. Prop. Drug. Rex. 54:25, 2000. Olivier. B., Soudijn, \V., and van Wujngaanden. I.: Serotonun. dopatitinc and norepinephnne transporters in the central nervous systetit and their inhibitors. Prop. Drug. Res. 54:59. 21)0(1. Xiiing. .1-N.. and Lee. 3. C.: Pharmacology of runnahinoid receptor agonists md aniugimists. Anna. Rep. Med. ('hem. 54:199. 2(8(11.

CHAPTER 16 Adrenergic Agents RODNEY L JOHNSON

Adrenergic drugs are chemical agents that exert their princi-

groups situated ortho to each other, the same arrangemern

pal pharmacological and therapeutic effects by either enhancing or reducing the activity of the various components of the sympathetic division of the autonomic nervous system. In general, substances that produce effects similar to stimulation of sympathetic nervous activity are known as svrnpaihwnimerks or udrenergk stin,,,lants. Those that de-

of hydroxyl groups as found in catechol. Aromatic corn

crease sympathetic activity arc referred to as synipatholyrie.c.

an::adrenergws. or adrenergw-hlockmg agents. Because of the important role that the sympathetic nervous system plays in the normal functioning of the body, adrenergic drugs find wide use in the treatment of a number of diseases. In addition

pounds that contain such an arrangement of hydroxyl subsiit

uents are highly susceptible to oxidation. such as epinephrine and NE. undergo oxidation in the ence of oxygen (air) or other oxidizing agents to produce ertho-quinone-like compounds. which undergo further rvac lions to give mixtures of colored products. Hence. of catecholamine drugs often are stabilized by the of an antioxidant (reducing agent) such as ascorbic acid cr sodium bisulfite.

to their effects on sympathetic nerve activity, a number of adrenergic agents produce important effects on the central nervous system (CNS). In this chapter. those agents that affect adrenergic neurotr.msmission and those that act directly on the various types of adrenergic receptors are dis-

Catethol

ortho-Quinone

cussed.

Epinephrine and NE each possess a chiral carbon atom. thus, each can exist as an enantionieric pair of isomers. enantiomer with the (R) configuration is biosynthesized

ADRENERGIC NEUROTRANSMITFERS

the body and possesses the biological activity. Catecholamines are polar substances that contain acidic (the aromatic hydroxyls) and basic (the aliphJtk amine) functional groups. For example, the pK, values the cpinephrine cation are 8.7 and 9.9 and are attributed

Structure and Physicochemlcal Norepinephrine (NE) is the neurotransmitter of the postgan-

glionic sympathetic neurons. As a result of sympathetic nerve stimulation, it is released from sympathetic nerve end-

ings into the synaptic cleft, where it interacts with specific presynaptic and posisynaptic adrcncrgic receptors. Another endogenous adrenergic receptor agonist is epinephrine. This compound is not released from peripheral sympathetic nerve endings, as is NE. Rather, it is synthesized and stored in the

adrenal medulla, from which it is released into the circulation. Thus. epinephrine is often referred to as a neurohormone. Epinephrine is also biosynthesized in certain neurons of the CNS. whcre both it and NE serve as neurotransmiters.

OH

H,

the phenolic hydroxyl group and the protonated group, respectively. Ganellin1 calculated the relative popuL

tions of the various ionized and nonionized species of and epincphrine at pH 7.4 and found that the cation loin (Fig. 16-IA) is present to an extent slightly greater than for both catecholamines. The zwittcrionic form (Fig. lb-Il, in which the aliphatic amine is prolonated and one of tic phenolic hydroxyl groups is ionized, is present to about Thus, at physiological pH. less than 2% of either cpinephtin.

or NE exist.s in the nonionized lbrm. This largely accouv' for the high water soluhility of these compounds as welin other catecholamines. such as isoproterenol and doparniin

Biosynthesis The biosynthesis of the catecholurnines dopamine. NE

H

A

CH3

Epinephrine and NE belong to the chemical class of substances known as the eateehok,,n,ne.s. This name was given

a sequence of enzymatic reactions: illustrated in Figure 16-2. Catecholamine biosynthesis lain place in adrenergic and dopaminergic neurons in the

in sympathetic neurons of the aut000mic nervous

slen

and in the adrenal medulla. The amino acid m.-tyrosine as the precursor for the camecholamines. It is tmnspurv;

to these compounds because they contain an amino group

actively into the axoplasm. where it is acted on by 3-monooxygenase (tyrosine hydroxylase) to form droxyphenylulanine (m.-dopu). Tyrosine hydroxylase is.

attached to an aromatic ring that contains two hydroxyl

Fe2

524

-containing enzyme thai requires molecular oxvgenac

Chapter 16 •

A

B

OH

OH

Figure 16—1 • Cationic (A) and zwitterionic (B) forms of norepinephrine CR = I-I) and epinephrine CR = HO

CH3)

Tyrosine Tyrosifle Hydroxylase

I

HO L-Dihydroxypheflytalafllfle I L-Aromatlc AmIno Acid 98

uses tetrahydrobioplcrin as a cofactor. The enzyme plays a key role in the regulation ot catecholainine biosynthesis, as it is the rate-limiting step. For example. adrenergic nerve stimulation leads to activation of a protein kinase that phosphorylates tyrosine hydroxylase. thereby increasing its activity. In addition, through end-product inhibition, NE markedly reduces tyrosinc hydroxylase activity. The basis of this feedback inhibition is believed to be a competition between the eatecholamine produci and the pterin cofactor. second enzymatic step in catecholamine biosynthesis is the decarboxylation of i.-dopu to give dopamine. The enzyme that carries out this transformation is i-aromatic amino acid decarboxylase (dopa decarboxylase). It is a cytoplasmic enzyme that uses pyridoxul phosphate as a cofactor. In addition to being found in catccholaminergic neurons, i-aromatic amino acid decarboxylase is Ibund in high concentrations

in many other tissues, including the liver and kidneys. It exhibits broad substrate specillcity, in that aromatic amino acids, such as L-tyrosine. L-phenylalanine. i-histidine. and i.-tryptophan. in addition to L-dopa and i.-5-hydroxytryptophan. serve as substrates.

The dopamine formed in the cytoplasm of the neuron is actively transported into storage vesicles. where it is hydroxylated stereospecilically by the Cu2 '-containing enzyme doto (dopamine pamine requires molecular oxygive NE, Dopamine It exhibits rather gen and uses ascorbic acid as a

HO

wide substr4te specificity. The NE formed is stored in the vesicles until depolarization of the neuron initiates the process of vesicle fusion with the plasma membrane and extnlsion of NE into the synaptic cleft. Adenosine Lriphosphate (ATP) and the protein chromogranin A arc released along with NE. In the adrenal medulla. NE is converted to epinephrine. This reaction, which involves the transfer of a methyl group from S-adenosyl methionine to NE. is catalyzed by phenylethanolumine-N-methyltransferase (PNMT). It occurs in the cytoplasm, and the epinephrine formed ix transported into

Dopamlne

Dopamine

OH NH2

HO

the storage granules of the chromaffin cells. Although

Norepinephrine

I pi,enyiethanofamine1N-methyltransferase

PNMT is highly localized in the adrenal medulla, it is also present in small amounts in heart and brain tissues.

Uke and Metabolism OH 3

HO Eplnephrine FIgure 16—2 • Biosynthesis of the cat&holamines dopamine, and epunephrine.

The action of NE at adrenergic receptors is terminated by a combination of processes, including uptake into the neuron and into extrancuronal tissues, diffusion away from the synapse. and metabolism. Usually, the primary mechanism for

termination of the action of NE is reuptake of the catecholamine into the nerve terminal. This process is termed uptake-I and involves a Na /C1-dependent transmemhrune transporter that has a high affinity for NE.4 This uptake systern also transports certain amines other than NE into the

526

Wilson and Gisiold'.s

Te.v Shook (JJ

Clwn,is,rv

Organid Piled,e:,,a! and

nerve lemiinal. and it can be blocked by such drugs as cocaine and sonic of the tricyclic antidepressants. Sonic of the NE that reenters the sympathetic neuron is transported into storage granules. where it is held in a stable complex with

ATI' and protein until sympathetic nerve activity or some other stimulus causes it to be released into the synaptic cleft.

The transport of NE from the cytoplasm into the storage granules is carried out by an H -dependent transincmbrane vesicular transporter.5 In addition to the neuronal uptake of NE discussed above. there exists an extraneuronal uptake process. uptake-2. This uptake process is present in a wide variety of cells. including

glial. hepatic. and myocardial cells. It has relatively low affinity for NE. Although its physiological significance is unknown, it may play a role in the disposition of circulating catecholamines. since catecholamines that are taken up into extraneuronal tissues arc metabolized rapidly. The two principal enzymes involved in catecholamine mc-

tabolism are monoamine oxidase (MAO) and catechol-OBoth of these enzymes are methyltransferase COMT).6 distributed throughout the body. with high concentrations found in the liver and MAO is associated primarily

with the outer membrane of the mitochondria. while COMT is found primarily in the cytoplasm. The wide tissue distribution of MAO and COMT indicates that both act on catecholamines that enter the circulation and the extrancuronal after being released from nerves or the adrenal gland or ahrr being adtninistered exogenously. In addition, the fact than COMT is not present in sympathetic neurons whereas the neuronal mitochondria do contain MAO indicates that MAO also has a role in the metabolism of intraneuronal catcehola mines. Neither COMT nor MAO exhibits high substrate specif c-

ity. MAO oxidatively deaminates a variety of that contain an amino group attached to a terminal carbon. There arc two types of MAOs. and these exhibit different substrate selectivity.5 For example. MAO-A shows substranc

preference for NE and serotonin. while MAO-B strale selectivity for and beniylaniine. Similarly. COMT catalyzes the niethylation of a variety ii catechol-containing molecules. The lack of substrate sped-

ficity of COMT and MAO is manifested in the metabolic disposition of NE and epinephrine. shown in Figure 15.3 Not only do both MAO and COMT use NE and epinephninc

1) MAO

HO

Dehydrogenase

34.Dlhydroxypheflyl. glycolaldehyde

Norepinephrlne: A = H

A CH3

HO... Aldehyde Reductase

OH

H

COMT

OH

HO H A

OH

HO

HO 3.Methoxy-4.hydroxy. phenylethylene Glycol

3-Methoxy-4-hydroxymar,delic Acid

Figure 16—3 • Metabolism of norepinephrine and epinephrine by MAO and COMT.

Chapter 16 • as substrates, but each also acts on the metabolites produced by the other. The results of extensive research on catecholuminc metabolkm indicate that in the adrenergic neurons of human brain

and peripheral tissues, NE is deaminated oxidatively by MAO to give 3.4-dihydroxyphenylglycolaldehyde. which then is reduced by aldehyde reductase to 3.4-dihydroxyphen-

ylethylene glycol. It is primarily this glycol nietubolite that is released into the circulation, where it undergoes methylalion by the COMT that it encounters in nonneuronal tissues.

The product of methylation. 3-methoxy-4-hydroxyphenylethylene glycol, is oxidized by alcohol dehydrogenase and aldehyde dehydrogenase to give 3-methoxy.4-hydroxymandelic acid. This mnetabolite commonly is referred to as vanil-

lylmandelic acid (VMA). and although it can be the end product of several pathways of NE metabolism. 3-methoxy-

4-hydroxyphenylethylene glycol is its principal precursor. In the oxidative deamination of NE and epinephrine at extraneumnal sites such as the liver, the aldehyde that is formed is onidized usually by aldehyde dehydrogenase to give 3,4lihydroxymandelic acid.

Methylation by COMT occurs almost exclusively on the neza.hydroxyl group of the catechol. regardless of whether

he catechol is NE. epinephrine. or one of the metabolic products. For example. the action of COMT on NE and epincphiine gives normetanephrine and metanephrine. respec-

lively. A converging pattern of NE metabolism of NE and epinephrine in which 3.methoxy-4-hydroxymandclic acid and 1.methoxy-4-hydroxyphenylethylene glycol are common end products thus occurs, regardless of whether the lint metabolic step is oxidation by MAO or methylation by COMT.

I

Under normal circumstances. 3-methoxy-4-hydroxyniandelic acid is the principal urinary naetabolite of NE. though substantial amounts of 3-methoxy.4-hydroxyphenylethylene

are excreted along with varying quantities of other

I

nactabolites. both in the free form and as sulfate or glucuronije conjugates. Endogcnous epinephrine is excreted primarlv as

I

nietanephrine and 3.methoxy-4-hydroxymandelic

aid.

ADRENERGIC RECEPTORS

nAdrenergic

Receptors

Ahiquist" was the Iirst to propose the existence of two gcnad types of adrenergic receptors (adrenoceptors) in mamitalian tissues. He designated these adrenergic receptors a ijsI His hypothesis was based on the differing relative çstencies of a series of adrenergic receptor agonists on variros smooth muscle preparations. In the early I 970s. the that certain adrenergic agonists and antagonists exhibited various degrees of selectivity for presynaptic and Issisynaptic a-adrenergic receptors led to the proposal that

susisynaptic a receptors be designated a1 and that presynap-

a receptors be referred to as Later, a functional dassification of the a receptors was proposed wherein a1 receptors were designated as those that were excitatory.

I

527

synaptic and either excitatory or inhibitory in their responses. Thus, it became clear that neither an anatomical nor a functional classification system was as generally useful

in classifying adrenergic receptors as a pharmacological classification based on the relative potency of a series of receptor agonists and antagonists.'2 Pharmacological and molecular biological methods have shown that it is possible to subdivide the a1 and a2 receptors into additional subtypes. Although the subtyping of adrenergic receptors continues to evolve, at present, the a1 and a2 receptors each have been divided into at least three subtypes. which have been designated alA. a18, a10 and a25, a28. a20-. respectively)' The molecular basis by which activation of a-adrenergic receptors produces the appropriate tissue responses has been

studied extensively. Both receptor subtypes belong to a superfamily of membrane receptors whose general structure consists of seven transniembrane a-helical segnients and whose signal-transduction mechanisms involve coupling to guanine nucleotide-regulatory proteins (C) proteins). They differ from each other, however, in the second-messenger The a,-adrenergic receptor is system that is coupled to the enzyme phospholipase C via a C) protein. Gq. When stimulated by activation of the a,-adrenergic receptor. phospholipase C hydrolyzes phosphalidylinositol-4.5-bisphosphate to give the second messengers mositol- I .4,5-tn-

phosphate Ilnst l.4.5)P,j and 1.2-diacylglycerol (DAG). lns( I ,4,5)P, stimulates the release of Ca2 from the sarcoplasmic reticulum, while DAG activates protein kinase C. an enzyme that phosphorylates proteins, a, -Receptor activation also can increase the intlux of extracellular Ca1 via voltage-dependent as well us non—voltage-dependent Ca2

channels. Activation of a2-adrencrgic receptors leads to a reduction in the catalytic activity oladenylyl cyclase. which in turn results in a lowering of intracellular levels of cyclic3.5-adenosine monophosphate (cAMP). The a2-adrenergic receptor—mediated inhibition of adenylyl cyclase is regulated by the G protein G,. a-Adrcncrgic receptors of the CNS and in peripheral tissues affect a number of important physiological functions." In particular, a receptors are involved in control of the cardiova.scular system. For example. constriction of vascular smooth muscle is mediated by both postjunctional a1- and a2-adrenergic receptors, though the predominant receptor In the heart, activation of a1 mediating this effect is receptors results in a selective inotropic response with little or no change in heart rate." This is in contrast to the /3, receptor, which is the predominant postjunctional receptor in the heart, mediating both inotropic and chronotropic effects. In the brain, activation of postjunctional a2 receptors reduces sympathetic outflow from the CNS. which in turn causes a lowering of blood pressure.21' The prototypical a2 receptor is the presynaplic a receptor found on the terminus of the sympathetic neuron)" 11.21 Interaction of this receptor with agonists such as NE and epiuiephrine results in inhibi-

tion of NE release from the neuron. The a2 receptors not only play a role in the regulation of NE release but also

shile a1 receptors purportedly mediated inhibitory revines." Further developments revealed, however, that

regulate the release of other neurotransmitters. such as acetylcholinc and serotonin. Both a1- and a2-adrenergic receptors also play an important role in the regulation of a number of metabolic processes, such as insulin secretion and glyco-

both a1 and a2 receptors could be either presynaptic or post-

genolysis.22

528

al Or,ç'wiie tledici,wl and Plwrsnaeeuncal Che,,,iszrv

Wilson and Gi.o'old'.s

fi-Adrenergic Receptors

of the receptor interact with the 0, protein.

In 1967. almost 20 years atier Ahlquist's landmark paper proposing the existence of a- and receptors.

aspartic acid residue 113 in transmembrane region Ill acts the countcrion to the cationic amino group of the adrcnergk agonist, while two serine residues, at positions 204 and 207 in transniembranc region V. form hydrogen bonds with

Lands et al.23 suggested that

vided into flu and

receptors also could be subdi-

types. Seventeen years later. Arch ci

al.24 identified a third subtype ot/3 receptor in brown adipose tissue. They initially referred to this as an atypical fireceptor. but it later became designated the subtype.'5 These f3adrenergic receptor subtypes differ in tenOn ol the rank order of potency of the adrenergic receptor agonists NE. epinephrine. and isoproterenol. The receptors exhibit the agonist

potency order isoproterenol > epinephrine = NE. while receptors exhibit the agonist potency order isoproterenol > cpinephrine >> NE. For the receptor. the agonist potency order is isoproterenol = NE > epinephrine. The fi receptors are located mainly in the heart, where they mediate the positive inotropic and chronotropic effects ol' the catecholumines. They are also found on the juxt-aglouiierular cells of the kidney, where they are involved in increasing renin secretion. The receptors are located on smooth

muscle throughout the body. where they arc involved in relaxation of the smooth muscle, producing such effects as bronchodilation and vasodilation. They are also found in the liver, where they promote glycogenolysis. The receptor is located on brown adipose tissue and is involved in the stimulation of Iipolysis. Like the a,-udrcncrgic receptors, the fi-adrenergic receptors belong to the superfamily of membrane receptors whose general structure consists suf seven transmemhrane a-helical segments and whose signal-transduction mechanisms involve coupling to G proteins. All three fl-receptors are coupled to adenylyl cyclase. which catalytes the conversion of AlP to cAMP. This coupling is via the guanine nucleotide protein (3,25 In the absence of agonist. guanosine diphosphate (GDP) is hound reversibly to the (3, protein. Interac-

tion of the agonist with the receptor is believed to bring about a conlorniational change in the protein receptor, which causes a reduction in the affinity of the G, protein for CJDP and a concomitant increase in affinity for guanosine triphos-

phate (GTP). The a, subunit of the 0. protein, with GTP bound to it, dissociates front the receptor—G protein ternary

complex, hinds to adenylyl cyclase. atid activates the enzyme. The bound OTP then undergoes hydrolysis to GDP. and the receptor—G, protein complex returns to the basal state.

The intracellular function of the second-messenger cAMP appears to be activation of protein kinases. which phosphorylate specific proteins, thereby altering their function. Thus. the phosphorylated proteins mediate the actions of cAMP. which functions as the mediator of the action of the drug or neurotransinitter that originally interacted with the fl-recep-

tor.27 The action of cAMP is terminated by a class of enzymes known as phosphodiesterases. which catalyze the hy-

drolysis of cAMI' to AMP. Cloning of the gene and complementary DNA (eDNA) for the manimaliun fi-adrenergic receptor has made it possible to explore through single point mutations and the construction of chimeric receptors the structure—function relationships of the receptor.25 Through such studies, it has been proposed

that the adrenergic agonist-binding site is within the transmembrane-spanning regions. while the cytoplasmic regions

catechol hydroxyls of the adrenergic agonists. The droxyl group of adrenergic agonists is thought to form hydrogen bond with the side chain of asparagine 293 a transmembrane region Vi. while the phenylalaninc at position 290 in the same transmemhrane region is heliescd

to interact with the catechol ring. Information such as this will no doubt aid in the future design and synthesis of new and improved adrenergic receptor agonists and antagonusx Molecular biological techniques have shown the existenm of adrenergic receptor polymorphism for both the a- and

adrenergic receptors. It is postulated that such polymw phisms may be an important factor behind individual diffa• ences in responses to drugs acting at these receptors. Also. there may he an association between the adrenergic receptor genes and disease states.2" This will 1

tainly be an active area of research in the future, and results could have a great impact on the development and therapeutic use of not only the current adrenergic agents but also those that arc yet to be developed.

DRUGS AFFECTING ADRENERGIC NEUROTRANSMISSION

Drugs Affecting Catecholamlne Biosynthesis Metyrosine.

Many agents that affect

bioxynthe.sis are known, hut only a few are used u.s therupcu

tic agents. Metyrosinc (a-rnethyl-i-tyrosine, example of a catecholamine-hiosynthesis inhibitor in Metyrosine differs structurally from tyrosine only a the presence of an a-methyl group. It isa connpetitive

tor of tyrosine hydroxyla.se. the first and rate-limiting in catecholamine biosynthesis. As such. nnetyrosine Is much more effective inhibitor of epinephrine and NE jxs' duction than agents that inhibit any of the other enaytla involved in catecholannine biosynthesis. Although melyro sine is used as a racemic mixture. it is the (—) isomer possesses the inhibitory activity. Metyrosine. which is orally in dosages ranging from I to 4 glday. is used pririo pally for the preoperative tnanagement of toma. This condition involves chromaffin cell tumors thx produce large amounts of NE and epinephrine. Althou4 these tumors, which occur in the adrenal medulla, are obuc

benign. patients frequently

hypertensive episondo

Metyrosine reduces the frequency and severity of these

sodes by significantly lowering catecholamine (35 to ((0%). The drug is excreted mainly unchanged isle urine. Because of its limited solubility in water. crystallat is a potential serious side effect. Sedation is the most mon side effect of metyrosine.

C'H3CO2H Metyrosine

DTugs Affecting Catecholamlne Storage

whole root of R.xerpeniina are used in the treatment of

and Release

hypertension. Preparations in which reserpine is combined with a diuretic also are available, as diuretics increase the efficacy of reserpine.

Reserpinc is the prototypical drug affecting the vesicle storage of NE in sympathetic neurons and neuions of the CNS and of epinephrine in the adrenal medulla. ho actions are not limited to NE and epinephrine. however. as it also affects the storage of serotonin and dopamine in their respective neurons in the brain. Reserpine is an indole alkaloid obtained from the root of serpenlina. a climbing shrub found in India. Other alkaloid constituents of this plant that possess pharmacological activity similar to that of reserpine are deserpidine and rescinnamine. ReserReserpine.

binds extremely tightly with the ATP-driven monoamine transporter that transports NE and other biogenic This amities from the cytoplasm into the storage pine

binding leads to a blockade of the transporter. Thus in sympathetic neurons. NE. which normally is transported into the storage vesicles. is instead metabolized by mitochondrial MAO in the cytoplasm. In addition, there is a gradual loss of vesicle-stored NE as it is used up by release resulting lion sympathetic nerve activity. It is thought that the storage eventually become dysfunctional. The end result is

i depIction of NE in the sympathetic neuron. Analogous cifects are seen in the adrenal medulla with epinephrine and in serotonergic neurons.

Guanethidine and GuanadreL

Neuronal blocking agents arc drugs that produce their pharmacological effects primarily by preventing the release of NE from sympathetic nerve terminals. Drugs of this type enter the adrenergic neuron by way of the uptake-I process and accumulate with in the neuronal storage vesicles. There, they stabilize the neuronal storage vesicle membranes, making them less respon-

sive to nerve impulses. The ability of the vesicles to fuse with the neuronal membrane is diminished, resulting in inhibition of NE release into the synaptic cleft. Some of these agents on long-term administration also can produce a depletion of NE stores in sympathetic neurons. Structurally, the neuronal blocking drugs typically possess a guanidino moiety ICNHC( = NH)NH2I, which is attached to either an alicyclic or an aromatic lipophilic group. These structural features are seen in guancthidine (Ismelin) and

guanadrel (Hylorel). which are used clinically in the treatment of hypertension. The presence of the very basic guanidmo group (pK,> 12) in these drugs means that at physiolog-

ical pH they are essentially completely protonated. Thus. these agents do not get into the CNS.

Guanethidine OCR3 Renerpine: A' = OCR3. A2 =

OCH3

Guanadrel

OCR3

=H, R2= OCR3 OCR3

Rt = OCH3. R2 = OCH3

When reserpinc is given orally. it maximum effect is seen

Although guanethidine and guanadrel have virtually the same mechanism of action on sympathetic neurons, they differ in their pharmacokinetic properties. For example. while guanethidine is absorbed incompletely after oral administration (3 to 50%).panadrel is well absorbed, with a bioavailability of 85cf.3 These two agents also differ in terms of half-life: Guanethidine has a half-life of about 5 days, whereas guanadrel has a half-life of 12 hours. Both agents are partially metabolized (—50%) by the liver, and both are used to treat moderate-to-severe hypertension. either alone or in combination with another antihyperlensive agent.

a couple of weeks. A sustained effect up to several is seen after the last dose has been given. Reserpine

ii otensively metabolized through hydrolysis of the ester unction at position 18. This yields methyl reserpate and acid. As is typical of many indole utkaktds. reserpine is susceptible to decomposition by light

ad oxidation. Both the pure alkaloid and the powdered

Bretylium Tosylate.

Another neuronal blocking agent is the aromatic quaternary ammonium compound bretylium tosylate (Bretylol). This agent is used as an antiarrhythmic drug. Its antiarrhythmic actions are not believed to be due to its neuronal blocking effects, however. This agent is discussed in more detail in Chapter 19.

530

IViIst,n and Gi.cr,dds Texthuo& of Organic Medki,,a! and Pharinaceulkal Chemistry

CH3

+1

Q— Br

CH2 —N—CH2CH3 CH3 Bretyllum Tosylate

SYMPATHOMIMETIC AGENTS Sympnthomimetic agents produce effects resembling those produced by stimulation of the sympathetic nervous system. They may be classified as agents that produce effects by a direct, indirect, or mixed mechanism of action. Direct-acting agents elicit a sympathomimelic response by interacting directly with adrenergic receptors. Indirect-acting agents pro-

duce effects primarily by causing the release of NE from adrenergic nerve terminals: the NE that is released by the indirect-acting agent activates the receptors to produce the response. Compounds with a mixed mechanism of action interact directly with adrenergic receptors and cause the release of NE. As described below, the mechanism by which an agent produces its sympathomimetic effect is related intimately to its chemical structure.

Direct-Acting Sympathominietics STRUCTURE—ACTIVITY RELATIONSHIPS

Structure—activity relationships for a- and /3-adrenergic receptor agonists have been The parent structure for many of the sympathomimetic drugs is /3-phenylech-

ylamine. The manner in which /3-phenylethylamine

is

substituted on the mew and para positions of the aromatic ring and on the amino, a. and $ positions of the ethylaminc side chain influences not only the mechanism of sympathomimetic action but also the receptor selectivity of the drug. For the direct-acting sympathomimetic amines. maximal activity is seen in /3-phenylechylamine derivatives containing hydroxyl groups in the mew and para positions of the aromatic ring (a catechol) and a $-hydroxyl group of the correct stereochemical configuration on the ethylamine portion of the molecule. Such structural features are seen in the prototypical direct-acting compounds NE. epinephrinc. and isoprotcrcnol.

A critical factor in the interaction of adrenergic agonists with their receptors is stereoselecciviry. Direct-acting sympa-

thomimetics that exhibit chirality by virtue of the presence of a /3-hydroxyl group (phenylethanolamines) invariably exhibit high stereoselectivity in producing their agonistic effects; that is. one enantiomeric form of the drug has greater

affinity for the receptor than the other form has. This is tote for both a- and /3-receptor agonists. For epinephrine. NE and related compounds, the more potent enantiomer has fit (R) configuration. This enanciomer is typically several 1(N). fold more potent than the enanhiomer with the (S) configura. Lion. It appears that for all direct-acting. /3-phenyl. ethylamine-derived agonists that are structurally similar ii NE, the more potent enantiomer is capable of assuming conformation that results in the arrangement in space of the cacechol group, the amino group, and the /3-hydroxyl group in a fashion resembling that of (— )-(Rl-NE. This explanation of stereoselectivity is based on the presumed interaction these three critical pharmacophoric groups with three cion plementary binding areas on the receptor and is known a' the Easson-Stedinan hypothesis.'7' 36 This three-point action is supported by recent site-directed mutagenesis stud' ies2° on the adrenergic receptor and is illustrated in Figure 16-4.

The pre.sence of the amino group in phenylethylamines is important for direct agonist activity. The amino group should be separated from the aromatic ring by two carbon atoms for optimal activity. Both primary and secondary amines air found among the potent direct-acting agonists, but tertiary or quatentary amines tend to be poor direct agonists. The nature of the amino substituent dramatically affect.s the in. ceptor selectivity of the compound. In general. as the bulkol the nitrogen substituentincrea.ses. a-receptor agomst decreases and /3-receptor activity increases. Thus NE. which is an effective /3,-receptor agonist, is also a potent and a potent agonist at a,

tors. lsoproterenol. however. isa potent and agonist but has little affinity for a receptors. The nature the substituent can also affect /3, - and

selectivity.

In several instances, it has been shown that an

Asp113 Figure 16—4 • Illustration of the Easson-Stedman hypothies

representing the interaction of three critical pharmacophr: groups of norepinephrine with the complementary areas on the adrenergic receptor as suggested by mutagenesis studies,

Chapter 16 S Adretiergie

seketi vity. For example, N-terl-hutyl norepinephrine Coltcrol) is 9 to 10 times as potent an agonist receptors. Large receptors than at cardiac tracheal

show selectivity to the

cubstituents on the amino group also protect the amino group

oral bioavailability.

group enhances

531

receptor. As in the case of the

resorcinol niodification. this type otsubstitution gives agents that are not nuetaboli/ed by COMT and thus show improved

front undergoing oxidative deamination by MAO. OH

NHCH(CH3)2 NHCH(CH3)2

OH Isoproterenol

Resorcinal OH

Metaproterenol

OH NH(CH3)3

NHC(CH3)3

N-tert-Butylnorepinephrine (Colterol)

Methyl or ethyl substitution on the a-carbon of the ethside chain reduces direct receptor agonist activity at both a and $ receptors. Importantly, however, an a-alkyl group increases the duration of action of the phenylethylamagonist by making the compound resistant to metabolic

&amination by MAO. Such compounds often exhibit enhanced oral effectiveness and greater CNS activity than their counterparts that do not contain an a-alkyl group. a-Substilulion also significantly affects receptor selectivity. In the for example. a-methyl or ethyl substitu-

CH2OH Albuterol

Modification at the catechol ring can also bring about selectivity at a receptors as it appears that the catechol moiety is more important tar agonist activity at receptors than at a1 receptors. For example. removal of the p-hydroxyl group from epinephrine gives phenylephrine, which, in contrast to epinephrine. is selective for the a1-adrenergic receptor.

lion results in compounds with selectivity toward the th rceeptur. while in the case of a receptors, a-methyl substituion gives compounds with selectivity toward the recep-

or, Another effect of a-substitution is the introduction of a center, which has pronounced effects on the stereoclvrnieal requirements for activity. For example, with a-

it is the e:'thro (IR.2S) isomer that significant activity at a receptors. H,

OH NH2

Phenylephrine

In addition to the /3-phenylethylamine class ot adrenergic receptor agonists. there is a second chemical class of compounds. the irnidaiolines. that give rise to a-adrenergic receptor agonists. These imidazolines can be nonselective. or they can be selective for either the a1- or a2-adrenergie re-

ceptors. Structurally, imidaiolines for the most part have the heterocyclic imidazoline nucleus linked to a substituted (1 R,2S).a.Methylnoreplnephrine

Although the catechol moiety is an important structural caure in terms of yielding compounds with maximal agoactivity at udrenergic receptors, it can be replaced with phenyl moieties to provide selective adrencrgic agonists. In particular, this approach has been used in design of selective /32-receptor agonists. For example.

aromatic moiety via sonic type of bridging unit (Fig. 16Although modification of the imidazoline ring generally results in compounds with significantly reduced agonist activity, there are examples of so-called open-ring imidai.olines that are highly active. The optimum bridging unit (X) is usually a single amino or methylene group. The nature of the aromatic moiety. as well u.s how it is substituted, is quite

cplxemenl of the catechol function of isoproterenol with heresoreinol structure gives the drug nietuproicrenol. which a celective

agt)nist. Furthermore, since the

triorvinol ring is not a substrate for COMT, /3 ugonists that asitain this ring structure tend to have better absorption hataL-Icristics and a longer duration of action than their cateJuil-containing counterparts. In another approach, replacescOt of the mew-hydroxyl of the catechol structure with a group gives agents. such u.s albuterol, which

N

Aromatic moiety

N H

Imldazoline nng

Bridging unit

Figure 16—5 • General structural features of the imidazoline a-adrertergic receptor agonists.

532

tVj/.cc,,, and Gino/d.c 'lexihook of Organie Medleinal arid

flexible. However, agonist activity is enhanced when the aromatic ring is substituted with halogen substituents like Cl or small alkyl groups like methyl, particularly when they are placed in the two orliw positions. Since the structure—activity relationships of the imidazolines are quite different it has been postufrom those of the lated that the imidazolines interact with a-adrenergic recep-

tors differently from the way the particularly with regard to the aromatic

do.

(i,emixtn' oxidizing agents, and oxygen of the air. It is not effecticu by the oral route because of poor absorption and rapid metab-

olism by MAO and COMT. Although intravenous infusion of epinephrine has pronounced effects on the cardiovascular system, its use iii thc

treatment of heart block or circulatory collapse is limited because of its tendency to induce cardiac arrhythmias. It increases systolic pressure by increasing cardiac output, and

it lowers diastolic pressure by causing an overall

ENDOGENOUS CATECHOLAMINES

in peripheral resistance; the net result is little change in incas blood pressure. Epinephrine is of value as a constrictor in hemorrhage us

The three naturally occurring catecholamines dopamine. NE, and epinephrine are used as therapeutic agents.

nasal congestion. Also, it is used to enhance the of local anesthetics, Its use in these two situations take'

Dopamine.

advantage of the drug's potent stimulatory effects on a icreceprro ceptors. The ability of epinephrine to stimulate

Dopamine is used in the treatment of shock.

It is ineffective orally, in large part because it is a substrate for both MAO and COMT. Thus, it is used intravenously. In contrast with the catecholamines NE and epinephrine, dopamine increases blood flow to the kidney in doses that have no chronotropic effect on the heart or that cause no increase in blood pressure. The increased blood flow to the kidneys enhances glomerular filtration rate. Na' excretion. and, in turn, urinary output. The dilation of renal blood vessels produced by dnpaminc is the result of its agonist action on the o1-dopamine receptor.

has led to its use by injection and by inhalation to relax bronchial stnooth muscle in asthma and in anaphylactic rca'tions. Several over-the-counter preparations (e.g.. Pri-

matene. Bronkaid) used for treating bronchial asthma epinephrine. Epinephrine is used in the treatment of open-angle glaucoma, where it apparently reduces intraocular pressure

increasing the rate of outflow of aqueous humor from its anterior chamber of the eye. The irritation often experienced

on instillation 01' epinephrinc into the eye has led to its development of other preparations of the drug that potentially are not as irritating. One such example is dipiveiris

Doparnine

Dipivefrmn. l)ipivefrin (dipivalyl epinephrine, is a prodrug of epinephrine that is formed by the esteritic.u Lion of the catechol hydroxyl groups of cpincphrine with

pivalic acid. Dipiveirin is much more lipophilic than

In doses slightly higher than those required to increase receptors of renal blood flow, dopamine stimulates the the heart to increase cardiac output. Some of the effects of dopamine on the heart are also due to NE release. Infusion

ncphrine. and it achieves much better penetration of the when administered topically as an aqueous solution for the treatment of primary open-angle glaucoma. It is

at a rate greater than 10 sag/kg per minute results in stimulaLion of a1 receptors, leading to vasoconstriction and an increase in arterial blood pressure.

Dipivefrin offers the advantage of being less irritating

epincphrmne by esterases in the cornea and anterior chamber

the eye than cpincphrine. and because of its more efficiec transport into the eye, it can be used in lower concentraliuw than epinephrine.

NE (Levophed) is used to maintain blood pressure in acute hypotensive states resulting from

0

Noreplnephrine (NE,).

OH

surgical or nonsurgical trauma, central vasomotor depres. sion. and hemorrhage. Like the other endogenous catechola-

mines, it is a substrate for both MAO and COMT and thus is not effective by the oral route of administration. It is given by intravenous injection.

Epinephrine.

0

Dipivefrin

Epinephrine (Adrenalin) finds use in a

number of situations because of its potent stimulatory et'fects on both a- and fl-adrenergic receptors. Like the other cate-

cholamines, epinephrine is light sensitive and easily oxidized on exposure to air because of the catcchol ring system. The development of a pink to brown color indicates oxidative breakdown. To minimize oxidation, solutions of the drug are stabilized by the addition of reducing agents such as sodium bisulfite. As the free amine, it is used in aqueous solution for inhalation. Like other amines, it forms salts with acids; for example, those now used include the hydrochloride and the bitartrate. Epinephrine is destroyed readily in

alkaline solutions and by metals (e.g.. Cu. Fe. Zn). weak

Esterases

Epinephnne

+

2 (CH3)3CCO2H

a-ADRENERGIC RECEPTOR AGONISTS

Phenylephrine.

(Neo-Synephrüc Phcnylephrine structure shown above under "Structure—Activity Relatioxships") is the prototypical selective direct-acting a potent vasoconstrictor but is less potent

Chapter 16 • and norcpincphrine (NE). It is active when given orully. and its duration or action is about twice that of epincphrine. II is metabolized by MAO. hut since it lacks the catecliol moiety, it is not metabolized by COMT. It is relatimely nontoxic and produces little CNS stimulation. When applied to mucous membranes, it reduces congestion and oiclling by constricting the blood vessels of the membranes. Thus, one of its maul uses is in the relief of nasal congestion. In the eye, it is used to dilate the pupil and to treat open-angle glaucoma. It also is used in spinal anesthesia, to prolong the

533

Naphazoline. Tetrahydrozoline, Xy!ometazollne, and Oxymetazo!Ine. 'rite 2-aralkylimidazolines naphazoline (Privinc). Ictrahydrozoline (Tyzine. Visine). sylometazoline (Otrivin). and oxymctazoline (Airin) are agonists at both ar and a2-adrencrgic receptors. These agents arc used

for their vasoconsfrictivc effects as nasal and ophthalmic decongestants. They have limited access to the CNS. since they essentially exist in an ionized at physiological pH because of the very basic nature of the imidazoline ring lpK. 9 to 10).

anesthesia and to prevent a drop in blood pressure during he procedure. Another use is in the treatment of severe hypolension resulting from either shock or drug administration. Methoxamine. Another selective direct-acting a1-receptor agonist used therapeutically is meihoxamine (Vasoxyl). This drug is a vasoconstrictor that has no stimulant

on the heart. In fact, it tends to slow the ventricular rule because of activation of the carotid sinus reflex. It is

Naphazoilne: A =

—CH2.-—(")

U

ess potent than phenylephrine as a vasoconstrictor. Methoxamine is used primarily during surgery to maintain adequate anerial blood pressure. especially in conjunction with spinal anesthesia. ft does not stimulate the CNS.

OH

CH3O

Tetrahydrozoline: A =

\/

CH3 OCH3

H3C

Methoxamine Midodrine.

Oxymetazotine: A

Midodrinc (ProAmatine) reprcsems an-

other example of a dimechoxy-fl-phenylethylaniine derivatvr that is used therapeutically for its vasoconstrictor propcnics.Specilically, it is used in the treatment of symptomatic onhosialic hypotension. Midodrine is the N-glycyl prodrug if he selective a1 -receptor agonist desglyntidodrine. Removal of the N-glycyl moiety front tnidodrine occurs readily the liver as well as throughout the body, presumably by inñd,Lses.

H3C

OH

H3C Xylometazollne: A =

H3C

OH

CH3O

NHCOCH2NH2

C'Ionidine. Clonidiiie (Catapres) is an example of a (phenylimino)imidazolidinc derivative that possesses sekc-

tivity for the a2-adrenergic receptor. The al :a2 ratio is 3m): I. Under certain conditions, such as intravenous infusion. clonidine can briefly exhibit vasoconstrictive activity as a result of stimulation of peripheral a-adrencrgic receptors. However, this hypertensive effect, if ii occurs, is fol-

OCH3 Midodrine

CH3O

OH NH2

OCH3 Desglymidodrlne

lowed by a much longer lasting hypotensive effect as a result of the ability of clonidine to enter into the CNS and stimulate a2 receptors located in regions of the brain, such as the nucleus tractus solitarius. Stimulation of these r, receptors brings about a decrease in sympathetic outflow from the CNS. which in turn leads to decreases in peripheral vascular resistance and blood pressure.211 Bradycardia is also produced by clonidine as a result of a centrally induced facilitation of the vagus nerve and stimulation of cardiac prejunctional a2-adrenergic receptors.°° These phamiacological actions have made clonidine quite useful in the treatment of hypertension.

534

Wil.vv.n, u,,d Gisva!dx Tr'abooL of Organic Medkmna! and Pharmactwica! Chemistry

half-life of clonidinc ranges from 20 to 25 hours, while thai flirguanfacine is about 17 hours. Guanabenz has the duration of action of these three agents. with a half-life of about 6 hours. Clonidine and guanfacine are excreted un-

changed in the urine to the extent of 60 and 50%. tively. Very little of guanabenz is excreted unchanged in urine. Clonidine: A = H 4-Hydroxyclonidine: A = OH Apraclonidine: A = NH2

The ot do and its an antihypertensive effect depends on the ability of these compounds not only to interact with the receptor but also to gain entry into the CNS. For example. in the case of clonidine, the hasicity of the guanidine group (typically pK, 3.6)

Guanabenz

I

is decreased to 8.0 (the pK. of clonidine) because of its direct

attachment to the dichlorophenyl ring. Thus, at physiological pH. clonidine will exist to a significant extent in the nonionized form required for passage into the CNS.

Substitutions on the aromatic ring also affect the ability of clonidine and its analogues to gain entry into the CNS to produce an antihypertensive effect. Although various halogen and alkyl substitutions can be placed at the two art/la positions of the(phenylimino)imidazolidine nucleus without affecting the affinity of the derivatives toward a2 receptors. such substitutions have a marked effect on the lipophilicity of the compound. Halogen substituents such as chlorine seem to provide the optimal characteristics in this regard.4° This distributive phenomenon is seen with one of the nietabolites of clonidine. 4-hydroxyclonidine. This compound has good affinity for a! receptors, but since it is too polar to get into the CNS. it is not an effective antihypcrtcnsivc agent. In addition to binding to the a2 adrenergic receptor. clonidine, as well as some other imidazolines. shows high affinity for what has been termed the "irnidazoline" Some studies have implicated a role for the imidazoline receptors in the antihypertensive effects of clonidine.43 However, other studies involving both site-directed mutagenesis of the tr!A-adrenergic receptor subtype and genetically engineered knockout mice deficient in either the a2Kor a2,5-adrenergic receptor subtypes provide evidence that the hypotensive response of the a2-receptor agonists like

clonidine primarily involves the a!A-adrencrgic receptor subtype.45

Guanabenz and Guanfadne. Two analogues of clonidine. guanabenz (Wytensin) and guanfacine (Tenexi. are also used as antihypertensive drugs. Their mechanism of action is the same as that of clonidine. Structurally, these two compounds can be considered "open-ring imidazolidines." In these compounds. the 2,6-dichlorophenyl moiety found in clonidine is connected to a guanidino group by a two-atom bridge. In the case of guanabenz. this bridge is a —CH = N— group, while lbr guanfacine it is a —CH2CO— moiety. For both compounds, conjugation of the guanidino moiety with the bridging moiety helps to decrease the pK.

Guanfacine

Apraclonidine and Brimonidine.

In addition In therapeutic use as an antihypertensive agent. clonidine hibeen found to provide beneficial effects in a situations.47 These include migraine prophylazis.

opiate withdrawal syndrome. and anesthcsia. Thio hiprompted the development of analogues of clonidine cific use in some of the above areas. Two such exampk

arc apraclonidine (lopidine) and brimonidine Both are selective a7-receptor agonist.s with 30:1 and 1.000:1. respectively. They both lower intra,salr pressure by decreasing aqueous humor production and in creasing aqueous humor outflow. Apraclonidine is cifically tocontrol elevations in intraocular pressuretllatc2! occur during laser surgery on the eye. Brimonidine alse I used in such a manner: in addition, it is approved

treating glaucoma. Another example is tlzanidine ILi natlex). which finds use in treating spasticityas.cociatedsii

multiple sclerosis or spinal cord injury. By stimulating adrenergic receptors. it is believed to decrease the of excitatory amino acid neurotransmitters from spinal ar-I inlemeurons.45

çN

Br

Brlmonldlne

of this normally very basic group so that at physiological pU-I a significant portion of each drug exists in its nonionized form. Differences between clonidine and its two analogues

N.,,N

are seen in their elimination half-life values and in their metabolism and urinary excretion patterns. The elimination

Tizanldlne

H

Chapter 16 • itdreneri,qc A phenylethylamine derivative that shows selectivity toward the a1 receptor is a-methylnorepinephrine (Fig. 16-6). As discussed above under "StrucUN—Activity Relationships." the presence of an a-methyl

umup in the correct configuration on the phenylethylamine nucleus yields compounds with increased potency at a2 receptors and decreased potency at a1 receptors. Although amcthylnorepinephrinc is not given as a drug. it is the metaholic product of the drug methyldopa (i-a-methyl-3.4-dihydroxyphenylalanine. Aldornet). Since inethyldopa is a close %uuctural analogue of I -dopa. it is treated as an alternate substrate by the enzyme L-aromatic amino acid decarboxylasc. The product of this initial enzymatic reaction is a-meth)ldopanline. This intermediate, in turn, is acted on by dopa-

mine fl-hydroxylase to give the diastercoisomer of awhich possesses the (R) configuragroup and the (S) non at the carbon with the configuration at the carbon with the a-methyl substituent Fig. 16-6). Ii is postulated that a-methylnorcpincphrine acts on receptors in the CNS in the same manner as clonidine.

to decrease sympathetic outflow and lower blood pressure.38 Since methyldopa serves as an alternate substrate to i-ammatic amino acid decarboxylase. it ultimately decreases the concentration of dopamine. NE. epinephrine, and serotonin in the CNS and periphery.

Methyldopa is used only by oral administration since its zwitterionic character limits its solubility. Absorption can range from S to 62% and appears to involve an amino acid transporter. Absorption is affected by food, and about 40% of that absorbed is converted to methyldopa-O-sulfate by the mucosal intestinal cells. Entry into the CNS also appears to involve an active transport process. The ester hydrochloride salt of methyldopu. methyldopate (Aldotnet ester), was developed as a highly water-soluble derivative that could be used to make parenteral preparations. Methyldopate is converted to methyldopa in the body through the action of esterases (Fig. 16-6). DUAL a- AND f3-ADRENERGIC RECEPTOR AGONISTS

Dobutamine.

NH3CI

HO I

Ho Methyktopate Esterases

There are synthetic direct-acting sympathomirnetics whose therapeutic use relies on their ability to receptors. One example is act at both a- and dobutamine (Dobutrex). Structurally. dobutamine can be viewed as an analogue oldopamine in which a l-(rnethyl)3-(4-hydroxyphenyl)propyl suhstitucnt has been placed on the amino group. This substitution gives a compound that possesses an asymmetric carbon atom. Thus, dobutamine exists as a pair of enantiorners. with each enantiomer possessing a distinct pharmacology.49 The ( + I enantiomer is a potent full agonist at both and f32 receptors. In contrast, the (—) enantiomer is some 10 times less potent at and th receptors. The (—) enantiorner is. however, a potent agonist at a1 receptors. Dohutarnine does not act as an agonist at the dopamincrgic receptors that mediate renal vasodilation.

CH3CO2H H

Methyldopa L-Aromatic Amino Acid Decarboxylase

HO

CH3 Dobutamine

In vivo, raceinic dobutamine increases the inotropic activ-

CH3 a-Methyldopamlne

ity of the heart to a much greater extent than it increases chronotropic activity. This pharmacological profile has led to its use in treating congestive heart failure. Since

recep-

tors are involved positively in both inotropic and chronoDopamine

H, OH

(1 R,2S)-a

FIgure 16—6 • Metabolic conversion of methyldopate and to a-methylnorepinephrine.

tropic effects of the heart, the selective inotropic effect seen with dobutamine cannot simply be due to its activity at receptors. Rather, this effect is the result of a combination

of the inotropic effect of (+ )-dohutarnine on receptors and that of (—)-dobutamine mediated through a1 receptors.°° Thus, this is a case where a racemic mixture provides a more desirable pharmacological and therapeutic effect than would either enantiomer alone. Dobutamine is given by intravenous infusion, since it is not effective orally. Solutions of the drug can exhibit a slight pink color as a result of oxidation of the catechol function. It has -a plasma half-life of about 2 minutes, It is metabolized

by COMT and conjugation but not by MAO.

536

WiAo,, and Gi.ci'okls Textbook of Organic Medicinal and Pl,arnwceu,ical Cherni.vtrv

Albuterol, Pirbuterol. and Salmeterol.

RECEPTOR AGONISTS

lsoproterenoL

Isoproterenol (Isuprel. structure shown above under "Structure—Activity Relationships") is the prototypical f3-ndmnergic receptor agonist. Because of an isopropyl substitution on the nitrogen atom, it has virtually no effect on a receptors. However. it does act on both /3, and receptors. It thus can produce an increase in cardiac output by stimulating cardiac /9, receptors and can bring about bronchodilation through stimulation of receptors in the respiratory tract. It also produces the metabolic effects expected of a potent /3 agonist. Isoproterenol is available for use by inhalation and injection. Its principal clinical use is for the relief of bronchospasms associated with bronchial asthma. In fact, it is one of the most potent bronchodilators available. Cardiac stimulation is an occasionally dangerous adverse effect in its use. This effect of isoprotercnol on the heart is sometimes made use of in the treatment of heart block. After oral administration, the absorption of isoproterenol is rather erratic and undependable. The drug has a duration of action of Ito 3 hours after inhalation. The principal reason for its poor absorption characteristics and relatively short duration of action is its facile metabolic transformation by sulfate and glucuronide conjugation of the ring hydroxyls and methylation by COMT. Unlike epinephrine and NE. isoproterenol does not appear to undergo oxidative deamination

by MAO. Since it is a catechol, it is sensitive to light and

Albuterol

(Proventil, Ventolin, structure shown above under "Stntctore—Activity Relationships"), pirbuterol (Maxair). and sol. metcrol (Serevent) are examples of selective /32-receptorag.

onists whose selectivity results from replacement of the ineta-hydroxyl group of the catechol ring with a methyl moiety. Pirbuterol is closely related structurally to albuterol; the only difference between the two is that pirbut. erol contains a pyridine ring instead of a benzcne ring. Ar in the case of metaproterenol and terbutaline, these drop arc not metabolized by either COMT or MAO. instead. they are conjugated with sulfate. They thus are active orally. and they exhibit a longer duration of action than isoproterenol. The duration of action of terbutaline. albuterol. and pirbut.

erol is in the range of 3 to 6 hours. OH

CH2OH Pirbuterol

OH

air. Aqueous solutions become pink on standing. The problems of lack of /3-receptor selectivity and rapid metabolic inactivation associated with isoproterenol have been overcome at least partially by the design and development of a numberof selective /32-adrenergic receptoragonists. These agents relax smooth muscle of the bronchi. uterus, and skeletal muscle vascular supply. They lind their primary use

as bronchodilators in the treatment of acute and chronic bronchial asthma and other obstructive pulmonary diseases.

Metaproterenol and Terbutaline.

As pointed out iii

the discussion of structure—activity relationships. modification of the catechol portion of a /3 agonist has resulted in the development of selective /32-receptor agonists. For example, metaprolerenol (Alupent. structure shown above under Relationships") and terbutalinc (Bricanyl. Brethine) are resorcinol derivatives that are /32 selective. Mctaprotcrcnol is less /32 selective than either terbutaline or

albuterol. Although these agents have a lower affinity for 132 receptors than isoproterenol. they are much more effec-

tive when given orally, and they have a longer duration of action. This is because they are not metabolized by either

COMT or MAO. Instead, their metabolism primarily involves glucuronide conjugation. Although both metaproterenol and terbutaline exhibit significant /32-receptor selectivity, the common cardiovascular effects associated with other adrenergic agents can also be seen with these drugs when high doses are used.

CH2OH Satmeterol

Salmeterol is a partial agonist at receptors and has potency similar to that of isoproterenol. It is very long (12 hours), an effect attributed to the lipophilic substituent on the nitrogen atom, which is believed to act with a site outside but adjacent to the active site. Thi agent associates with the /32 receptor slowly and dis.sociatcr

from the receptor at an even slower rate."

Foimoterol and Levalbuterol.

Another long-acting

/32-receptor agonist is Formoterol (Foradil). Its long durjiitr

of action, which is comparable to that of salmctcrol, ha been suggested to result from its association with the men brane lipid Formoterol has a much faster oust, si action than does salmetcrol. Both of these long-acting drug.

are used by inhalation and are recommended for nance treatment of asthma, usually in conjunction with a inhaled corticosteroid. OH (RS)

H

NI-ICHO Formoterol Terbutatine

All of the above /32-receptor agonists possess at least ow chinul center and are used as racemic mixtures. Fonnoteal

Chapter 16 •

Agesus

537

possesses two chiral centers and is used as the racernic mixture of the (R.R) and (S.S) enantiomers. As mentioned above. it is the (R) isomer of the phenylethanolumines that possesses

fetal distress caused by excessive uterine activity. Its uterine inhibitory are more sustained than its effects on the

the phannacological activity. Concerns have been raised

those caused by nonsclective $ agonists. The cardiovascular

about the use of such racenaic mixtures under the belief that the inactive (SI isomer may he responsible for some of thc

effects usually associated with its administration are mild

effects seen with these agents. Levalbuterol (Xopenex). the (RI isomer of racemic albuterol. represents the

it is administered initially by intravenous infusion to stop

cardiovascular system, which arc minimal compared with

tachycardia and slight diastolic pressure decrease. Usually.

premature labor. Subsequently. it may be given orally.

first attempt to address this issue.

OH H

Isoetha rifle. Another sympathomimetic drug that finds use as a bronchodilator is the a-ethyl catecholamine, isoetha-

rinc. This agent is weaker than isoproterenol at stimulating n.'ceptors. In addition, its selectivity is not us great as hat seen with drugs such as terbutaline oralhutcrol. Because ol the presence of the a-ethyl group. isoetharine is not metaboli,cd by MAO. Because it contains the cacechol ring system. howevcr. it is metabolized quite elTectively by

cOMT. It also is 0-sulfated quite effectively. Isoetharine a duration of action similar to that of isoproterenol.

CH3

Ritodrine

th-Adrenergic Receptor Agonists. acting agonists for the

Selective direct-

receptor have been de-

veloped, hut they have not been approved for therapeutic Because stimulation of the receptor promotes lipolysis. these agents may have potential as antiobesity drugs and as drugs for the treatment of non—insulin-dependeni diabetes.

Indlrect-Acflng Sympathomimeths Isoethanne

Bitolterol (Tornalate) is a prodrug of the Bitolterol. sclective adrenergic agonist colterol. the N-ier:-butyl anahsgue of NE. The presence of the Iwo p-toluic acid esters in bitolterol makes it considerably more lipophilic than colterol. Bitoherol is administered by inhalation for bronchial asthma and reversible hronchospa.srn. It is hydrolyzed by esterases in the lung and other tissues to produce the active

agent, cotterol. Bitolterol has a longer duration of action than isoproterenol (5 to 8 hours) and is nsetaboliied. after hydrolysis of the esters, by COMT and conjugation. OH

Bitottorol

Indirect-acting sympathomimetics act by releasing endogenous NE. They enter the nerve ending by way of the activeuptake process and displace NE from its storage granules. Certain structural characteristics tend to impart indirect sympathomimetic activity to phenylethylainines. As with the direct-acting agents. the presence of the catechol hydroxyls enhances the potency of indirect-acting phenylethylamines. However, the indirect-acting drugs that are used therapeutically are not catechol derivatives and, in most cases, do not even contain a hydroxyl moiety. In contrast with the directacting agents, the presence of a $-hydroxyl group decreases. and an a-methyl group increases, the elfectiveness of indirect-acting agents. The presence of nitrogen substituents decreases indirect activity, with substituents larger than methyl rendering the cotnpound virtually inactive. Phenylethylamincs that contain a tertiary amino group are also ineffective u.s NE-releasing agents. Given the foregoing structure—activity considerations, it is easy to understand why amphetamine and p-tyramine are often cited as prototypical indirect-acting sympathotnimetics. Since amphetamine-type drugs exert their primary effects on the CNS. they are discussed in tnore detail in Chapter IS. This chapter discusses those agents that exert their effects primarily on the periphery.

2H

OH +

2

CH3 Colterol

Acid

Ritodrine (Yutopar) is a selective /32-receptoe agonist used to control premature labor and to reverse Ritodrine.

Amphetamine

Hydroxyamphetamine.

p-Tyramine

Although p-tyramine is not a clinically useful agent. its a-methylated derivative. hydroxyamphetamine (Puredrine). is an effective, indirect-acting sympathontimetic drug. Hydroxyatnphetamine has little or

538

Wilson and

Textbook of Organir Med it'inal and Pliurn:aceuiical Chemistry

no ephedrinc-like. CNS.stimulating action. It is used to dilate the pupil for diagnostic eye examinations and for surgical procedures on the eye. It is used sometimes with choliner-

gic blocking drugs like atropine to produce a mydriatic effect, which is more pronounced than that produced by either drug alone.

Relative Pressor Activity of the Isomers of Ephedrine TABLE 16—1

Isomer Relative Activity 36

—

DL.t ± )-EpIK'siriflc

26

L-( + 1-Ephedrinc

II

-, ).Pseudoephedrinc

7

aL-I ± )-Pseudocptiedrinr

Hydroxyamphetamine

i.(+)-Pseudoephedrine. IA + )-Pscudoephedrine (Sudafed. Afrinol. Drixoral) is the (S.S) diastereoisomcr of cphedrine. It is a naturally occurring alkaloid from the Ephe' dra species. Whereas ephedrinc has a mixed mechanism of

action. pseudoephedrine acts principally by an indirect mechanism. The structural basis for this difference in mechanism is the stereochemistry of the carbon atom possessing the $-hydroxyl group. In pseudoephedrine. this carbon atom possesses the (S) configuration, which is the wrong stereochemistry at this center for a direct-acting effect at adrenergic receptors. This agent is found in many over-the-counter nasal decongestant and cold medications. Although ii is less prone to increase blood pre.ssure than ephedrine. it should

be used with caution in hypertensive individuals, and it should not be used in combination with MAO inhibitors.

4

— i-Pseudocphedñnc

I

stems of various species of Ephedra. Mahuang. the plant containing ephedrine. was known to the Chinese in 2,(X0) ac. hut the active principle. ephedrine. was not isolated 1885.

Ephedrine has two asymmetric carbon atoms; thus. thar

are four optically active forms. The o'r5-ihro raccmatc called "ephedrine." and the threo racemaic is known

Natural ephedrine is 'pseudoephcdrine" n(—) isomer, and it is the most active of the four isomers as a pressor amine (Table 16-I). This is largely due to the fact that this isomer has the correct (R) configuration at the carS

bon atom bearing the hydroxyl group and the desired (SI configuration at the carbon bearing the methyl group lot optimal direct action at adrenergic receptors.

OH

OH

CH3

CH3

L-(+)-Pseudoephedrlne

Propylhexedrine.

Propyihexedrine (Benzedrex) is an analogue of amphetamine in which the aromatic ring has been replaced with a cyclohcxane ring. This drug produces vasoconstriction and a decongestant effect on the nasal membranes, but it only about one-half the pressor effect of amphetamine and produces decidedly fewer effects on the CNS. Its major use is for a local vasoconsirictive effect on nasal mucosa in the symptomatic relief of nasal congestion caused by the common cold, allergic rhinitis. or sinusitis.

NH2

Propylhexedrine

With a Mixed Mechanism of Action Those phenylethylamines considered to have a mixed inechanism of action usually have no hydroxyls on the aromatic

D-(-).Ephednne

Ephedrine decomposes gradually and darkens when

posed to light. The free alkaloid is a strong base, and aqueous solution of the free alkaloid has a pH above 10 The salt form has a pK. of 9.6. The pharmacological activity of ephedrine resembles tici of epinephrine. The drug acts on both a- and f3-adrcnergt receptors. Although it is less potent than epinephrine. it' pressor and local vasoconsirictive actions are of greaterdurution. It also causes more pronounced stimulation oF the CNS

than epinephrine. and il is effective when given orally. Th; drug is not metabolized by either MAO or COMT. Rathet. it is p-hydroxyiated and N-demethylaled by cytochmrne P. 450 mixed-tbnction oxidases. Ephedrine and its salts are used orally, intravenously, tramuscularly. and topically for a variety of conditions. as allergic disorders, colds. hypotensive conditions, and nat' colepsy. It is used locally to constrict the nasal mucosu aai cause decongestion and to dilate the pupil or the branch Systemically, it is effective for asthma, hay fever, and srtl caria.

ring but do have a fl-hydroxyl group.

Phenylpropanolamine.

D-(—)-Ephedrine is the classic example of a sympathomimctic with a mixed mechanism of action. This drug is an alkaloid that can be obtained from the

drine) is similar in structure to ephedrine except thai ii primary instead of a secondary amine. This modificatir gives an agent that has slightly higher va.sopressivc and lower central stimulniory action than ephedrine. Its

D-(—.)-Ephedrine.

is

Phenyipropanolamine

Chapter 16 • lion as a nasal decongestant is more prolonged than that of ephedrine. It is effective when given orally. Phenylpropanoamine was a common active component in over-the-counter appetite suppressants and cough and cold medications until 2001, when the Food and Drug Administration (FDA) recommended its removal from such medications because studtea showed an increased risk of hemorrhagic stroke in young women who took the drug.

Age,,ts

539

ably, the antagonistic actions of these agents at presynaptic receptors contribute to their cardiac stimulant effects by enhancing the release of NE. Both agents have a direct vasodilatory action on vascular smooth muscle that may he more prominent than their a-receptor antagonistic effects.

OH Tolazotlne

oH3 Phenylpropanolamine

Metaraminol. Metaraminol (Araminc) is structurally to phenylephrine except that it is a primary instead of a secondary amine. It possesses a mixed mechanism of with its direct-acting effects mainly on a-adrenergic receptors. It is used parenlerally as a vasopressor in the treatment and prevention of the acute hypotensive state occurring with spinal anesthesia. It also has been used to treat severe hypotension brought on by other traumas that induce shock.

OH

OH3

OH Metaraminot

Phentotamine

The antagonistic action of tolazoline is relatively weak. but its histamine-like and acetylcholine-like agonistic actions probably contribute to its va.sodilatory activity. Its histamine-like effects include stimulation of gastric acid secretion, rendering it inappropriate for administration to patients who have gastric or peptic ulcers. It has been used to treat Raynaud's syndrome and other conditions involving peripheral vasospasm. Tolazoline is available in an injectable form and is indicated for use in persistent pulmonary hypertension of the newborn when supportive Uleasures are not successful.

Phentolamine is used to prevent or control hypertensive episodes that occur in patients with pheochromocytoma. It can be used as an aid in the diagnosis of pheochromocytoma. but measurement of catecholamine levels is a safer and more reliable method of diagnosis. It also has been used in combi-

ADRENERGIC RECEPTOR ANTAGONISTS

a.Adrenerglc

Receptor Antagonists

receptor antagonists, which hear dear structural similarities to the adrenergic agonists NE. Lnlike the

epinephrinc. and isoproterenol, the ce-adrenergic receptor anlagonists consist of a number of compounds of diverse chem.

cal structure that bear little obvious resemblance to the areceptor NONSELECTIVE a-RECEPTOR ANTAGONISTS

The agents in this class Toiazoline and PhentolamIne. are structurally similar to the irnidazoline a-agonists. such as naphazolinc. tetrahydrozoline. and xylometazoline. The

nation with papaverine to treat impotence. IRREVERSIBLE a-RECEPTOR BLOCKERS

Agents in this class, when given in adequate doses, produce a slowly developing, prolonged adrenergic blockade that is not overcome by epincphrine. In essence, they are irreversible blockers of the a-adrenergic receptor. Chemically, they

are f3-haloalkylamines. Although dibenamine is the prototypical agent in this class, it is phenoxybenzamine that is used therapeutically today.

Ph—\ N—CH2CH2CI

Ph—'

type of group attached to the imidazoline ring dictates whether an imidazoline is an agonist or an antagonist. The two representatives of the imidazoline a antagonists that are used therapeutically are tolazoline (Priscoline) and phentolamine (Regitine). Both are competitive (reversible) blocking agents. Phentolamine is the more effective a antagonist. hut

CH3

(J_-OCH2CH

neither drug is useful in treating essential hypertension. Theoretically, the vasodilatory effects of an a-antagonist be beneficial in the management of hypertension. Tolazoline and phentolamine. however, have both a1- and activity and produce tachycardia. Presum-

Phenoxybenzamlne

5.40

of ()rj,'anie tIet/iiina! anil Phar,,uwt,aica! (hemisin

tVll.so,, isiul

blocking acetykholine. histamine, and serotonin receptom. its primary pharmacological effects, especially vasodilation. may he attributed to its a-adrenergic blocking capability. As would be expected of a drug that produces such a profound (S

I Cl

R Aziridinlum Ion

Ii

blockade, administration is frequently associatcd with tachycardia. increased cardiac output. and postural hypoten. sion. There is also evidence indicating that blockade of pre. synaptic receptors contributes to the increased heart rjte produced by phenoxybeniamine. The onset of action of is slow, hut the effects of a single dose of drug may last 3 to 4 days. since essentially new receptors need to be made to replace that have been inhibited irreversibly. The principal effects following its administration are an increase in peripheral blood how, an increase in skin temperature, and a lowCrinf of blood pressure. it has no effect on the parasympathetic system and little effect on the gastrointestinal tract. The 11551

I

R'\+

common side effects are miosis. tachycardia. nasal stuff. CI —

,N1

A

Nu

ness. and postural hypotension. all of which are related iii the production of adrenergic blockade. Oral phenoxybetuamine is used for the preoperative maragement of patients with pheochromocylomu and in the chronic management of patients whose tumors art not naMe to surgery. Only about 20 to 30% of an oral dise is absorbed.

Reversible Drug Receptor Complex

SELECTIVE a,-RECEPTOR ANTAGONISTS

Prazosin. Terazosin, Doxazosin.

Alkylated Receptor

Figure 16—7 • Mechanism of inactivation of sr-adrenergic receptors by

One group of highl'.

selective a1-rcceptor antagonists are the quinazolines. Examples include prazosin (Minipress). tcrazosin (Hytrinl.and doxazosin (Cardura). Structurally, these three agents consi't of three components: the quinaeoline ring, the piperamle ring, and the acyl moiety. The 4-amino group on the quinalo line ring is very important for a1-rcceptoraflinity. Although prazosin. terazosin. and doxaiosin possess a piperazine moiety attached to the quinazoline ring, this group can k replaced with other heterocyclic moieties (e.g.. piperidire moiety) without loss of affinity. The nature of the acyl gisup has a significant effect on the pharmacokinetic propellics.' Quinazoline ring

}

The mechanism whereby produce a long-lasting, irreversible cr-adrenergic receptor blockade is depicted in Figure 16-7. The initial step involves the fornia-

ring

tion of an intennediate nziridinium ion (ethylene iminium ion), which then forms an initial reversible complex with the receptor. The positively charged aiiridinium ion electrophile then reacts with a nucleophilic group on the receptor, result-

ins in the formation of a covalent bond between the drug and the receptor. Although the aziridinium ion intermediate has long been believed to be the active receptor-alkylating species, it was not until 1976 that it was demonstrated unequivocally that the a,iridiniunt ions derived front dihenaminc and phenoxybenumine are capable of a-receptor alkylatiori.54

NH2

Prazosin: R

=

Terazosln: R

Phenoxybenzamine. The action of phenoxybenzamine (Dibenzyline) has been described as representing a "chemical synipathectomy" because of its selective blockade of the excitatory responses of smooth muscle and of the heart muscle. Although phenoxybenzamine is capable of

Doxazosin: R =

Chapter 16 • Adreiwrgie Agents

These drugs are used in the treatment of hypertension. They dilate both arterioles and veins. Agents in this class offer distinct advantages over the other a-blockers because hey produce peripheral vasodilation without an increase in heart rate or cardiac output. This advantage, at least in part. is attributed to the fact that prazosin blocks postjunctional a1 receptors selectively without blocking presynaptic a2 receptors. These agents also find use in the treatment of benign

541

thine is a selective antagonist ot the a1 receptor. The only difference between these two compounds is the relative stereochemistry of the carbon containing the carbomethoxy substituent. In yohimbine. this group lies in the plane of the alkaloid ring system, while in corynanthine. it lies in an axial position and thus is out of the plane of the rings.5"

pmstatic hyperplasia. where they help improve urine flow rates.

Although the adverse effects of these drugs are usually minimal, the most frequent one, known as thefirsl-dosepl,ennmenon. is sometimes severe. This is a dose-dependent ellect characterized by marked excessive postural hypotension and syncope. This phenomenon can be minimized by giving an initial low dose at bedtime. The main difference between prazosin. terazosin. and dox-

Yohimbine

aiosin lies in their pharmacokinetic properties. As menhoned above, these differences are dictated by the nature of the acyl moiety attached to the piperazine ring. A compariol these three agents with respect to their oral bioavail-

ability, half-life, and duration of action is shown in Table 6-2. These drugs are metabolized extensively, with the metabolites excreted in the bile. Tamsulosin.

H3CO2C

The aryl sulfonamide tamsulosin (Ho-

max) represents the first in the class of subtype selective a1-

receptor. which seems to predominate in the prostate. It is approved for treating benign prostatic hyperplasia. for which ii is administered once daily. Orthostatic hypotension may not bc as great with this agent as with the nonselective quin-

OH

Cotynanthlne

antagonists. It is selective for the

Yohimbine increases heart rate and blood pressure as a result of its blockade of a2 receptors in the CNS. It has been used experimentally to treat male erectile impotence.

aiolines.

Mlrtazapine. H

The tetracyclic mirtazapine (Remeron) is another example of an a-antagonist that shows selectivity for a2 receptors versus a1 receptors.51 Blockade of central

CH3

a2 receptors results in an increased release of norepinephrine and serotonin. This has prompted its use as an antidepressant. This agent also has activity at nonadrenergic receptors. It is

9

a potent blocker of 5-HT2 and 5-HT3 serotonin receptors and at histamine

Tamsulosln

I

receptors.

SELECTIVE te2-RECEPTOR ANTAGONISTS

Isomeric indole alkaYohimbine and cosynanthine. known as the yohimbanes exhibit different degrees of skctivity toward the a1- and a2-adrenergic receptors. deon their stereochemistry. For example. yohimbine selective antagonist of the a2 receptor. while corynan-

bids

Mlrtazapine

TABLE 16-2 Pharmacokinetic Properties of Prazosin, Terazosin. and Doxazosln

/3-Adrenergic Receptor Antagonists STRUCTURE-ACTIVITY RELATiONSHIPS

Agent

Bloavatlablllty

Half-life

(%)

(hours)

Duration of Action (hours)

2—3

4—6

(DCI). The structure of DCI is like that of isoproterenol.

90

')—t2

IS

except that the catechol hydroxyl groups have been replaced

22

36

by two chloro groups. This simple structural modification. involving the replacement of the aromatic hydroxyl groups.

P11J011fl

The first /3 blocker was not reported until 1958. when Powell and Slateras described the activity of dichloroisoproterenol

542

Wilson and Gisrold's Texibook of Orgwiie- Medicinal and Pharmaceutical Chemistry

has provided the basis for nearly all of the approaches used in subsequent efforts to design and synthesize therapeutically useful 13-receptor antagonists.35 Unfortunately. DCI is not a

type. Although it was not released for use in the United States, it was the first cardioseledive antagonist to be used extensively in humans. Because it produced several

pure antagonist but a partial agonist. The substantial direct sympathomimetic action of DC! precluded its development as a clinically useful drug.

toxic effects, however, it is no longer in general use in most countries.

NHCOCH3

Olchloroisoproterenol

Pronethalol was the next important 13 antagonist to be described. Although it had much less intrinsic sympathomimetic activity than DCI, it was withdrawn rrom clinical testing because of reports that it caused thymic tumors in mice. Within 2 years of this report, however. Black and Stephenson59 described the 13-blocking actions of propranolol, a close structural relative of pronethalol. Propranolol has become one of the most thoroughly studied and widely used drugs in the therapeutic armamentarium. It is (he standard against which all other p antagonists are compared.

Proneihalol

Practolol

As in the sympathomimetics. bulky aliphatic groups. such as the tert-butyl and isopropyl groups. are normally found tat the amino function of the aryloxypropanolaniine f3-recepwt antagonists. It must be a secondary amine for optimal an-

tivity. The 13-blocking agents exhibit high stereoselectivity inthc

production of their 13-blocking effects. As with the thomimetic agents, the configuration of the hydmxyl-bcsing carbon of the aryloxypropanolamine side chain playua critical role in the interaction of 13-antagonist drugs with fi receptors. This carbon must possess the (S) configumlicii for optimal affinity to the 13 receptor. The cnantiomer the (R) configuration is typically 100 times less potent. Th: available data indicate that the pharmacologically mote tive enantiomer interacts with the receptor recognition lii: in a manner analogous to that of the agonists. The structurul features of the aromatic portion of the antagonist. howeuct appear to perturb the receptor or to interact with it in a man-

ner that inhibits activation. In spite of the fact that all of the 13-antagonistic activity resides in one euiandotart. propranolol and most other 13 blockers are used clinical!

as racemic mixtures. The only exceptions are timolol. and penbutolol. with which the (SI enantiontet used.

Propranolol

Propranolol belongs to the group of 13-blocking agents known as aryloxypropanolasnine.c. This term reflects the fact that an —OCH2— group has been incorporated into (he mole-

cule between the aromatic ring and the ethylamino side chain. Because this structural feature is frequently found in 13 antagonists, the assumption is made that the —OCH2— group is responsible for the antagonistic properties of the molecules. However, this is not true: in fact, the —OCH-,— group is present in several compounds that are potent 13 ago-

NONSELECTIVE /3 BLOCKERS

Propranolol.

Propranolol (Inderal) is the pmlotypica 13-adrenergic receptor antagonist. It is nonselective in blocks the and 132 receptors equally well, like the other 13-receptor antagonists that arc discussed, lu competitive antagonist whose receptor-blocking be reversed with sufficient concentrations rently. propranolol is approved for use in the United Swtt for hypertension. cardiac arrhythmias. angina peetoris. ç4a

This latter fact again leads to the conclusion that it arosnat\c ting am\ its substituents tbat is nature ol is the primary determinant of 13-antagonistic activity. The aryl

nsyocardial infarction. hyperirophic

group also affects the absorption, excretion, and metabolism of the 13 blockers.6t

ment of a variety of other conditions. including

The nature of the aromatic ring is also a determinant in the flu selectivity of the antagonists. One common structural feature of many cardioselective antagonists is the pre.sence of a para substituent of sufficient size on the aromatic ring along with the absence of ,,zela substituents. Practolol is the antagonist of this structural prototypical example of a

anà

In addition. propranolol is tinder investigation for

trennt tic.

schizophrenia. alcohol withdrawal syndrome, and behavior. Some of the most prominent effects of propranolol ac the cardiovascular system. By blocking the /3 recepari the heart. propranolot stows the heart, reduces the fahx contraction, and reduces cardiac output. Because nt sympathetic activity and blockade of vascular

Chapter 16 • Adrei:crgic administration may result in increased peripheral resistance. The antihypertensive action, at least in part, may be attributed to its ability to reduce cardiac output. as well as to its

suppression of renin release from the kidney. Because it receptors, it is contraindicated exhibits no selectivity for in the presence of conditions such as asthma and bronchitis.

A facet of the pharmacological action of propranolol that has received a good deal of attention is us so-called membrane-stabilizing activity. This is a nonspecific effect (i.e., not mediated by a specific receptor), which is also referred to as a local anesthetic effect or a quinidine-like effect. Both cnantionlers possess membrane-stabilizing activity. Since the concentrations required to produce this effect far exceed those obtained with normal therapeutic doses of propranolol 2nd related /3-blocking drugs, it is most unlikely that the nonspecific membrane-stabilizing activity plays any role in he clinical efficacy of /3-blocking agents. The metabolism of propranolol has received intense study. Propranolol is well absorbed after oral administration, but ii undergoes extensive first-pass metabolism before it reaches the systemic circulation. Lower doses are extracted more efficiently than higher doses, indicating that the extracion process may become saturated at higher doses. In addition, the active enantiomer is cleared more slowly than the inactive cnantiomer!'2

Numerous metabolites of propranolol have been identifled, but the major metabolite in people, after a single oral kise. is naphthoxylactic acid, which is Formed by a series of metabolic reactions involving N-dealkylation. deamination, oxidation of the resultant aldehyde. One metabolite of interest is 4-hydroxypropranolol. This compound is a potent /3 antagonist that has some intrinsic sympathomi-

medc activity. It is not known what contribution, if any. 4hydroxypropranolol makes to the pharmacological effects seen after administration of propranolol. The half-life of propnno1o1 after a single oral dose is 3 to 4 hours, which inneases to 4 to 6 hours after long-term therapy.

543

lol (Carirol. Ocupress). timolol (Blocadren. Timoptic). levo-

bunolol (Betagan). sotalol (Betapace) and metipranolol (OptiPranolol). Structures of these compounds are shown in Figure 16-8. The first five of these agents arc used to treat hypcrtcnsion. Nadolol is also used in the long-term management of angina pcctoris. while timolol finds use in the prophylaxis of migraine headaches and in the therapy following myocardial infarction. Sotalol is used as an untiarrhythmic

in treating ventricular arrhythmias and atrial fibrillation because in addition to its /3-adrenergic blocking activity, this agent blocks the inward K current that delays cardiac rcpolari2ation. Carteolol, tirnolol. levobunolol. and melipranolol are used topically to treat open-angle glaucoma. These agents lower intraocular pressure with virtually no effect on pupil sue or accommodation. They thus offer an advantage over many

of the other drugs used in the treatment of glaucoma. Although the precise mechanism whereby /3 blockers lower intraocular pressure is not known with certainty, ii is believed that they may reduce the production of aqueous humor. Even though these agents are administered into the eye. systemic absorption can occur, producing such adverse effects as bradycardia and acute bronchospasm in patients with bronchospastic disease. Pindolol possesses modest menthrane-stahilizing activity and signiticant intrinsic /3-agonistic activity. Pcnbutolol and

carteolol also have partial agonistic activity hut not to the degree that pindolol does. The 13 antagonists with partial agonistic activity cause less slowing of the resting heart rate than do agents without this capability. The partial agonistic

activity may be beneficial in patients who are likely to exhibit severe bradycardia or who have little cardiac reserve. Timolol. pindolol. penbutolol. and carteolol have half-life values in the smue range as propranolol. The half-life of nadolol. however, is about 20 hours, making it one of the longest-acting /3 blockers. Timolol undergoes first-pass metabolism but not to the same extent that propranolol does.

Timolol and pcnbutolol are metabolized extensively, with little or no unchanged drug excreted in the urine. Pindolol is metabolized by the liver to the extent of 60%. with the remaining 40% being excreted in the urine unchanged. In contrast. nadolol undergoes very little hepatic metabolism. Most of this drug is excreted unchanged in the urine. Naphthoxylactic Acid

BLOCKERS

The discovery that /3-blocking agents are useful in the treatment of cardiovascular disease. such as hypertension, stimulated a search for cardioselective /3blockcrs. Curdioselective /3 antagonists are drugs that have a greater affinity ftr the receptors of the heart than for /32 receptors itt other tissues.

Such cardioselective agents should provide two important therapeutic advantages. The first advantage should be the

OH 4-Hydroxypropranolol

Other Nonselective /1 Blockers. Several other nonseItctis'e $blockers are used clinically. These include nadolol Curgani). pindolol (Visken). penbutolol (Levatol). carteo-

lack of an antagonistic effect on the /32 receptors in the bron-

chi. Theoretically, this would make blockers sak fuir use in patients who have bronchitis or bronchial asthma. The second advantage should be the absence of blockade of the vascular /3, receptors. which mediate vasodilation. This would be expected to reduce or eliminate the increase in peripheral resistance that sometimes occurs after the administration of nonselective /'3antagoiiists. Unlbrtunately. cardi-

544

IVllxoii and

Te.i.ibook

of Organi Medirinal and PI,armaeeiuicu! CJu.,ni.ar

H

0

Carteolol

Levobunolol

OH

OH

OCOCH3

Nadolol

Metipranolol

(bOH Plndo!ol

Penbutolol

OH

0'm N—S Timotol

Sotalol

Figure 16—8 u Nonseleclive

oselectivity is usually observed with

antagonists at only relatively low doses. At normal therapeutic doses, much of the selectivity is lost. At present, the following f31-selective agents are used ther-

apeutically: acebutolol (Sectral). atenolol (Tenormin). betaxolol (Kerlone. Betoptic). bi.soprolol (Zebeta). esmolol (Brevibloc). and metoprolol (Lopressor). Structures of these agents are depicted in Figure 16-9. All of these agents except

esmolol are indicated for the treatment of hypertension. Atenolol and metoprolol are also approved for use in treating angina pectoris and in therapy following myocardial infarction. Betaxolol is the only blocker indicated for the treatment of glaucoma. Acebutolol and csmolol are indicated for treating certain cardiac arrhythmias. Esmolol was designed specifically to possess a very short duration of action: it has an elimination half-life of 9 minutes. This agent is administered by continuous intravenous infusion for control of ventricular rate in

blockers.

patients with atrial flutter, atrial fibrillation, or sinus taclw cardia. Its rapid onset and short duration of action reakr ii useful during surgery, after an operation, or during can gency situations for short-term control of heart rates. fects disappear within 20 to 30 minutes after the infusiiii is discontinued. Esmolol must be diluted with an solution before administration: it is incompatible with v dium bicarbonate. The short duration of action of esmolol is the rcsuh s rapid hydrolysis of its ester functionality by esterases prcscs

in crythrocytes (Fig. 16-10). The resultant carboxylic is an extremely weak antagonist that does not appeal exhibit clinically signiticant effects. The acid metabolilek' an elimination half-life of 3 to 4 hours and is p• niarily by the kidneys. In the class of blockers, only sesses intrinsic sympathomimetic activity. This

very weak, however. Acehutolol and betaxolol

Chapter 16 a Adrent'rgic Agents

545

NHCH(CH3)2

CH2CONH2 Atonolol

Acebutolol

I'— CH2OCH2CH2OCH(CH3)2

CH2CH2OCH2 -
terfenadinc) as well.404' The advantages of this compound appear to he once-daily dosing, rapid onset of activity, minimal CNS effects, and a lack of clinically significant effects on cardiac rhythm when administered with imidazole antil'ungals and macrolide anti-

biotics. The onset of action is within 20 to 60 minutes in mosi patients. Cetirizine produce.s qualitatively different ci. fects on psychomotor and psychophysical functions from the first-generation antihistumines. The most common adverse reaction associated with cetirizine is dose-related somnolence, however, so patients should be advised that cetirizine may interiere with the performance of certain psychomotor and psychophysical activities Other effects of this drug in-

clude fatigue, dry mouth. pharyngilis. and dizziness. Be-

administered with imidazolc antifungals and macrolide antibiotics. Other typical drug interactions of H, antihisiamines, however, apply to cetirizinc. Concurrent use of this drug with alcohol and other CNS depressants should Lv avoided.4' Dose-proportional values are achieved within I hour of oral administration of celirizine. Food slows the rate of cetirizine absorption but does not affect the overall extent, Consistent with the polar nature of this carboxylic acid drug. less than 10% of peak plasma levels have been measuted in

the brain. Cetirizinc is not extensively metabolized, and more than 70% of a 10-mg oral dose is excreted in the urinc

Usual adult dose: Oral. 5—It) mg q.d. Dosage form: Tablets

Acrivastine, liSP.

form and alcohol and slightly soluble in water. Acrivastine is an analogue of triprolidine containing a car-

boxycthenyl moiety at the 6 position of the

ring.

Acrivastine shows antihistaminic potency and duration of action comparable to those of triprolidine. Unlike ttiprnlidine. acrivastine does not display significant anticholinergh activity at therapeutic concentrations. Also. the enlunccd

polarity of this compound resulting from substitution limits BBB penetration, and thus, this compound

produces less sedation than triprolidine.35 '" Limited pharmacokinetic data are available for thin compound. Orally administered drug has a hall-life of about hours and a total body clearance of 4.4 mUmin per kg. Tin

mean peak plasma concentrations are reported

NN Cetur,zine

Acrivastine, USP, (E.E)-3-16-I 1-14-

methylphenyl )-3-( I -pyrrolidinyl)- I -propenyl-2-pyridinyll2-propenoic acid (Semprex). is a fixed-combination of the antihistamine acrivastine (8mg) with the dccongcsrato pseudoephedrine (60 mg). Acrivastine is an odorless, ahile to pale-cream crystalline powder that is soluble in chiom'

AOH

0 Sat)

Chapter 21 • Histamine and A,uihistaminic Agents

widely, and the drug appears to penetrate the CNS poorly. The metabolic fate of acrivastine has not been reported.

715

also inhibit the chcmotaxis of eosinophils at the site of application (i.e.. ocular tissue). In lung tissue. pretreatment with the mast cell stabilizers cromolyn and nedocromil blocks the immediate and delayed bronchoconstrictive reactions induced by the inhalation of antigens. These drugs also attenuate the bronchospasm associated with exercise, cold air, environmental pollutants, and certain drugs (aspirin). The mast cell stabilizers do not have intrinsic bronchodilator, antihistamine. anticholinergic. vasoconstrictor. or glucocorticoid

H3C

activity and, when delivered by inhalation at the recommended dose, have no known therapeutic systemic activity. The structures, chemical properties. pharmacological protiles, and dosage data for these agents are provided in the monographs below.

COOH

Acrëvastine

0

adult dose: Oral. 8 or 60 mg t.i.d. to q.i.d. Dosage fonti: Tablets

KhelIin

cmmolyn Sodium,

USP. Crotnolyn sodium. disodium .3-his (2 -earboxychromon -5- yloxy ) -2-hydroxypropane (tntal). is a hygroscopic. white, hydrated crystalline powder that is soluble in waler (1:10). Ii is tasteless at first but leaves a very slightly bitter aftertaste. The of cromolyn is 2.0. It is available as a solution for a nebulizer, an aerosol spray. a nasal solution, an ophthalmic solution, and an oral concen-

INHIBITION OF HISTAMINE RELEASE: MAST CELL STABILIZERS

The discovery of the bronchodilating activity of the natural pnsiuct khetlin led to the development of the his(chromoncs) that stabilize mast cells and inhibit the release 01' histamine and other mediators of inflammation. The first therapeutically significant member of this class was cromoFurther research targeting more effective yn sodium.30 agents resulted in the introduction of nedocromil, followed asic recently by pemirolast and lodoxamide. Generally, the cell stahili,.ers inhibit activation of, and mediator refrom, a variety of inflammatory cell types associated with allergy and asthma, including cosinophils, neutrophils. mast cells, monocytes. and platelets. In addilion to histamine, these drugs inhibit the release ol' leuko(C4. D4. E4) and prostaglandins. In vitro studies sugthat these drugs indirectly inhibit calcium ion entry into mast cell and that this action prevents mediator release. In addition to their mediator release, some of these drugs

trate.

Nebulized and aerosol cromolyn is used for prophylactic management of bronchial asthma and prevention of exerciseinduced bronchospasm. Cromolyn nasal solution is used lbr

the prevention and treatment ol allergic rhinitis. and oral concentrate is used to treat the histaminic symptoms of mastocylosis (diarrhea, flushing, headaches, vomiting, urticana,

abdominal pain. nausea. and itching). In the treatment of asthtna. crotnolyn efficacy is manifested by decreased sever-

ity of clinical symptoms. or need for concomitant therapy, or both. Long-term use is justified if the drug significantly reduces the severity of asthma symptoms; permits a significant reduction in, or elimination of. steroid dosage; or inn-

COOeNB.

Na' OOC.

OCH2CHCH2O OH

Cromolyn Sodium

0

716

Wi/so,, and

Organic Medicinal and Pl,armuceu,ieal Chemistry

Textbook

The antiasthmittic effects of nedocromil may also invohc inhibition of axon reflexes. Axon reflexes may he producal by bradykinin in the presence of damage to the airway epi. thelium, resulting in release of sensory neuropeptides (sub. stance P. neurokinin A). which can produce hmnehrean•

proves management of those who have intolerable side effects to sympathomimetic agents or methylxanlhincs. For cromolyn to be effective, it must be adminislered at least 30 minutes prior to antigen challenge and administered at regular intervals (see dosing information below). Ovcruse of cromolyn results in tolerance.

striction and edema. Ncdocromil is more effective than crornolyn in reversing bradykinin-induced and neurokinin A—induced bronchoconstriction in humans.

Usual adult dose: Nebulizer solution. 20 mg inhaled q.i.d. Aerosol. 2 metered sprays inhaled q.i.d. Intranasal. 5.2 mg (one metered spray) in cach nostril lid, or q.i.d. at regular intervals Ophthalmic. I drop of a 2—4% solution q.i.d. toh times daily Oral. 2 ampules q.i.d. 30 minutes before meals and at bedtime

Usual adult dose: lntranasal. 14 mg 11W,' inhalutions) q.i.d at regular intervals

Lodoxamide Tromethamine.

signiticarn

and nedocromil is the presence of two acidic groups. Lodosamide Iromethamine. N.N'-( dioxamic acid (Alotuide). is a white crystalline. water-solu-

Nedocromil Sodium,

USP. Nedocromil sodium. disodium 9-ethyl-6.9-dihydro-4.6-dioxo- I 0.propyl.4H-pyrano I 3.2-glquinoline-2.8-dicarboxylate (Tilade). is available as an aerosol in a metered-dose inhaler.

ble powder. It is available as a 0.1% solution, with each milliliter containing 1.78 tug of lodoxamide tromethamine equivalent to I rng of lodoxamide. The solution contains the preservative bettzalkonium chloride (0.007w) as

Nedocromil is structurally related to cromolyn and displays similar, hut broader, pharmacological actions. Nedocromil is indicated for maintenance therapy in the management of patients with mild-to-moderate bronchial asthma. It was developed in a search for a compound with a better biological profile than cromolyn. which has limitations in the treatment of certain patients. such as the elderly asthmatic patient and patients with intrinsic asthma. Cromolyn is more effective in stabilizing connective tissue mast cells

as mannitol. hydroxypropyl methylcellulose. sodium citrate,

citric acid. edetate disodium. tyloxapol. hydrochloric acid and/or sodium hydroxide (to adjust pW. and puritied waler. Lodoxamide is indicated in the treatment of the (vcuku disorders including vemal keratoctitijunctivitis. vernal conjunctivitis, and vernal kcratitis.46 The dose for adults and children older than 2 years of age is I to 2 drops in cach affected eye 4 times daily lbr up to 3 months. The mist frequently reported ocular adverse experiences were tran sient burning, stinging. or discomfort on instillation.

than mucosal mast cells, and since release of mediators from mast cells in the lung is an important component of inflam-

mation and bronchial hyperreactivity in asthmatic patients. an agent with greater effects on mucosal mast cells was desirable. Available data suggest that nedocromil. although having profile of activity like that of cromolyn. is more effective in stabilizing mucosul mast cells.45 CH3CH2

The only

structurally similarity between lodoxamide and cmmulyn

Pemirolast Potassium Ophthalmic Solution.

Pemir.

ola.st can be considered an analogue of one portion of the crotuolyn structure in which the carboxyl group has been replaced with an isosteric tetrazole nioiety. Pemirola.st potas-

çH2cH2CH3

sium. 9.methyl-3-( IH-tetrazol-5-yl)-4H-pyridol I .2-al'pynmidin-4-one potassium (Alamast). is a yellow. water-solubic powder. The commercial preparation is available as a sterile ophthalmic solution for topical administration to tint eyes. Each milliliter of this solution Contains 1.0mg of pon irolast potassium. as well as the preservative lauralkonium chloride (0.005'7e). and glycerin, phosphate buffers, and sodium hydroxide to maintain a solution pH of 8.0. The ails. Lion has an osmolality of approximately 240 mOsnt/L, Tint recommended dose is one to two drops instilled into each affected eye 4 times a day. This drug product is for ocular administration only and not for injection or oral use. Pemiro'

COONa

N

0 Nedocromil Disodium

0

H

Ct

0

H

CH2OH

. HOCH2—C—NH2 0

CN

Lodoxamide Tromethamine

CH2OH

Chapter 21 •

717

and .4ntihi.ciwnjnic

last solution should be used with caution during pregnancy srwhile nursing, since its safety has not been studied under these circumstances.47

CH3

CI.

CH3

Pemirolast Potassium

Azelastine

The recommended dose of azelaslinc solution is rne drop instilled into each affected eye twice a day. This drug product is for ocular administration only and not for injection or oral use. Absorption of ae'.elastinc following ocular admninistra-

RECENT ANTIHISTAMINE DEVELOPMENTS:

non is relatively low (less than I ng/mL). Absorbed drug undergoes extensive oxidative N-demethylation by cylo-

ThE "DUAL-ACrING" ANTIHISTAMINES

chrome P-450. and the parent drug and mctabolite are elimi-

Over the past decade there has been considerable interest in

adverse reactions are transient eye burning or stinging, head-

he development of novel antihistaminic compounds with dual mechanisms of action including Hi-receptor antagonivnl and mast cell stabilization. Currently available drugs

aches, and bitter taste. Azelastine solution should be used with caution during pregnancy or while nursing, since its

nated primarily in the feces. The most frequently reported

safety has not been studied under these circumstances.45

that exhibit such dual antihistaminic actions include azelas-

line and ketotifen. These compounds contain the ba.sic phannacophore to produce relatively selective histamine H1 antagonism (diarylalkylamines) as well as inhibition

of histamine and other mediators (e.g.. and PAF) from mast cells involved in the

sI the

allergic response. In vitro studies suggest that these cantalso decrease chernotaxis and activation of casinothik. Azelastine and ketotifen currently are indicated for he treatment of itching of the eye associated with allergic

Their antiallergy actions occur within mmafter administration and may persist for up to 8 The structures, chemical properties. pharmacological preliles. and dosage data for these agents are provided in

Ketotifen Fumarate Ophthalmic Solution.

Ketotifen 4-( I-methyl -4-piperidylidene )-4H-beu,o(4,5 cycloheptal I .2-bithiophen- I 0(9H)-one hydrogen fumarate (Zaditor). is a fine crystalline powder. Ketotifeti is a ketofumarate.

I

thiophene isostere analogue of the dibenzocycloheptane an-

tihistamines. The solution contains 0.345 rng of ketotifen lumarate, which is equivalent to 0.25 mg of ketotifen. The solution also contains the preservative benzalkanium chloride (0.Ol'k) as well as glycerol, sodium hydroxide and/or hydrochloric acid (to adjust pH). and purified water. It has a pH of 4.4 to 5.8 and an osmolality of 210 to 30() mOsm/ kg.

the monographs below.

Azelas?Jne

Hydrochloride

Ophthalmic

Solution.

hydrochloride, (± )- I -(21I)-phthalazinone. 4-1(4lhlomphenyl)rnethyl I-2-(hexahydro-l -methyl-I H-azepin-4monohydrochloride (Optivar). is a shite crystalline powder that is sparingly soluble in water.

and propylene glycol and slightly soluble in cihanol. octanol. and glycerine. The commercial preparation available as a 0.05% sterile ophthalmic solution for topical aiministration to the eyes. Each milliliter of azelastine soluton contains 0.5 mg az.elastine hydrochloride equivalent to 1457 tag of azelastine base, the preservative benzalkonium Atoride iO.125 mg). and inactive ingredients including diso-

dihydrate, hydroxypropylmethylcellulose. sorhat solution, sodium hydroxide, and water for injection. The solution has a pH of approximately 5.0 to 6.5 and an nsrnolality of approximately 271 to 312 niOsmlL.

Ketotiten Fumarate

The recommended dose of ketotifen solution is one drop

instilled into each affected eye every 8 to 12 hours. The most frequently reported adverse reactions are conjunctival

718

Wilson

and Gisiold's Testbook of Organic Medicinal and Pharmaceutical Chemistry

injection, headaches, and rhinitis. This drug product is for ocular administration only and not for injection or oral use. Ketotifen solution should be used with caution during pregnancy or while nursing, since its safety has not been studied

acid and proteolytic pepsin enzymes, whose formation Ls facilitated by the low gastric pH. is generally assumed to be required for the hydrolysis of proteins and other foods.

under these circumstances.49

(oxyntic) cell. Parietal cells contain a hydrogen ion pump, a unique H10 + 1K -ATPase system that secretes H;O' in exchange for the uptake of K ion. Secretion of acid by gastric parietal (oxyntic) cells is regulated by the actions of various mediators at receptors located on the basolatenti membrane, including histamine agonism of H2 receptors (cellular), gastrin activity at G receptors (blood), and acetyl. choline (ACh) at M2 muscarinic receptors (neuronal) (Fif.

HISTAMINE H2 ANTAGONISTS Drugs whose pharmacological action primarily involves antagonism of the action of histamine at its H2 receptors find therapeutic application in the treatment of acid-peptic disorders ranging from heartburn to peptic ulcer disease, Zollinger-Ellison syndrome, gastroesophageal reflux disease (GERD), acute stress ulcers, and erosions.50'

The acid secretory Unit of the gastric mucosa is the

21.13).

Peptic Uker DIseaseU Peptide ulcer disease (PUD) is a group of upper Cl

Peptic Add Secretion A characteristic feature of the mammalian stomach is its ability to secrete acid as part of its involvement in digesting food for absorption later in the intestine. The presence of

tract

disorders that result from the erosive action of acid and pepsin. Duodenal ulcer (DU) and gastric ulcer (GIJ) are the most common forms, although PUD may occur in the esophaf us or small intestine. Factors involved in the pathogenesis and

Parietal Cell

K.

'Ci

H30'

). Histamine

Gastrin

I.

ACh

Endoc,lne Cell

Figure 21—13 • Hormonal regulation of acid secretion by parietal cells.

Chapter 21 • Histamine and Anzihistan,inic Age,,ls

recurrence of PUD include hypersecretion of acid and pepsin and GI infection by Helicobacter pylon, a Grain-negative spiral bacterium. H. priori has been found in virtually all patients with DtJ and approximately 75% of patients with Cli. Some risk factors associated with recurrence of PUD include cigarette smoking, chronic use of ulcerogenic drugs

nonsteroidal anti-inflammatory drugs INSAIDsI). male gender, age, alcohol consumption. emotional stress, and family history. The goals of PUD therapy are to promote healing, relieve pain, and prevent ulcer complications and recurrences. Mcdonions used to heal or reduce ulcer recurrence include antacids. histamine H2-receptor antagonists, protective mucosal (e.g.,

barriers, proton muth

pump inhibitors. prostaglandins. and bis-

salt and antibiotic combinations.

Sfructural Derivadon A review of the characterization and development of hista-

mine H2-receptor antagonists reveals a classic medicinal chemistry approach to problem solving.53 Structural evoluantagonist. tion of the first discovered, clinically useful cimetidine, is depicted in Figure 2l-l4. Methylation of the

5 position of the imidazole heterocycle of histamine produces a selective agonist at atrial histamine receptors (H2). The guanidino analogue of histamine possesses weak antagonist activity to the acid-secretory actions of histamine. Increasing the length of the side chain from two to four carbons, coupled with replacement of the strongly basic guanidino group by the neutrat methyl thiourea function. leads to burimamide. the first antagonist to be developed tacking detectable agonist activity in laboratory assays. The

STRUCTURE—ACTIVITY RELATIONSHIP

Histamine: H,

719

STRUCTURE

= 112

agonism

5-Methylhistamine: H2> H, agorrism

NH—C—NH2 Partial H2receptor agonist (weak antagonist)

CH2CH2— NH—C — NHCH3

Bunmamide: Full 112 antagonIst—

low potency, poor oral bioavailabllity

,pH2CH2— NH—C — NHCH3 S

Mellamide: Full H2 antagonist— higher potency, improved oral bloavailabllity, toxic (thiourea)

,PH2CH2— NH —C —NHCH3 Cimeddine: Full 112 antagonIst— higher potency, high oral low toxicity

Figure 21—14 • Structural derivation of histamine H2 antagonists.

NCN

720

tVllxon

GiX%okI'.s

Textbook of Orgwii Medici,ial wid Phurwaceulical Chemi.ctrs

low potency of burimamide is poswltued to be related to its nonhasic, electron-releasing side chain, which favors the

nonphannacophonc N't-H imidazole tautomer over the basic, electron-withdrawing side chain in histamine, which predominantly presents the higher-affinity N'-H imidazole (automer to the receptor. Insertion of an electronegative thioether function in the side chain in place of' a methylene

group favors the W tautomer. and imroduction of (he 5methyl group favors H2-rcceptor selectivity and leads to metiamide, a H2 blocker of higher potency and oral bioavailability than burimamide. Toxicity associated with the thiourea structural feature is eliminated by replacing the thiourea sulfur with a cyano-imino t'unction to produce cimetidine. Introduction of cimeudine into human medicine revealed an effective gastric antisecretory agent that promotes the healing olduodenal ulcers. Cimetidine is not without a num-

ber of limitations, however. Because it is short acting, it

aining functionality should be a polar. nonbasic substituent for maximal antagonist activity. Groups that are positiv civ charged at physiological pH appear to confer agonist activity. In general. antagonist activity varies inversely with the hydrophilic character of the nitrogen group. The hydrophilic group, I .1 -diaminonitroethene. found in ranitidine and niiatidine is an exception, however; it is much more active than is predicted by relative solubility

Cimetidine, USP. Cimetidine. 12.! 15-methylimidazol-4-ylmeihyl J-thio lethyl Iguanidinc (Tagamet), is a colorless crystalline solid that is slightly sole

ble in water (1.14% at 37°C). The solubility is greatly in creased by the addition of dilute acid to protonatc the imidaz-

of 6.8). At pH 7. aqueous

ole ring (apparent

are stable for at least 7 days. Cimelidine is a relatively hydm-

philic molecule with an octanol/water partition coefficient of 2.5.

requires a frequent-dosing schedule in humans, and in addi-

H3C\

tion, its selectivity is poor. Cimetidine has antiandrogenic activity, which can lead to gynecomastia. and it inhibits the cytochrome P450 mixed-function oxygenase-metabolizing enzyme system in the liver, an action that potentiales the

N

effects of drugs whose clearance also depends on biotrans-

/CH2SCH2CH2NH

C

N

formation by this system. Cimetidinc also causes confusinnal states in some elderly patients. Subsequent development of additional drugs 01' this class indicates that a great

deal of structural latitude is available in the design of H2 antagonists (Table 21.1

Examination of the structural features of H2 antagonists that came after cimetidine confirms that the imidazole ring of histamine is not required for competitive antagonism of histamine at H2 receptors. Other heterocycles may be used and may. in fact, enhance both potency and selectivity of H2-receptor antagonism. If the imidazole ring is used, how-H tautomer should be the predominant species ever. the for maximal H2-anlagonist activity. The electronic effects of the ring substituents and side-chain structural features determine the tautomerism. Separation of the ring and the nitrogen group with the equivalent of a four-carbon chain appears to be necessary for optimal antagonist activity. The isosteric thioether link is present in the fiur agents currently marketed in the United States. The terminal nirogen—con-

TABLE 21-1

Cimetidine

Cimetidine reduces the hepatic metabolism of drugs hiotransformed by the cytochrome P-450 mixed-oxidase tem, delaying elimination and increasing serum levels of these drugs. Concomitant therapy of patients with cimetidinc and drugs metabolized by hepatic microsomal enzymes. par.

ticularly those of low therapeutic ratio or in patients with renal or hepatic impairment. may require dosage adjustment Table 21.2 provides a compilation of drugs whose conihixi (ion therapy with cimetidine may increase their pharniaeological effects or toxicity. Antacids interfere with cimelidine absorption and should be administered at least I hour befoar or alter a cimetidinc dose. Cimetidine has a weak antiandrogenic effect, tia may occur in patients treated for I month or more. Cimetidine exhibits high oral hioavailability (60 to 70%t and a plasma half-life of about 2 hours, which is increased

Currentl y Available H2 Antagonists Dose

Orat

RelatIve Potency

Bloavaltablilty

MetabolIsm

(%)

Enzyme

Ciniciktine

t

63—78

FMO3

Famotidinc

-II)

37—45

7

10

98

7

6

52

EMO3: p.45))

Renal Clearance (Uhoun)

(%)

Route of ElimInation

Sutfoelde. hydrosymcthyt

—25

React

S'Osldc

—30

Renal

t4—26

—37

Renal

27-3s

—31)

Renal,

24—31

MetabolIzed

Metabolites

2-1-14

N2-o*idc Ranittdinc

E,om baum. 51.

Melabolic i)rng

N.Oxide. N.desmelliyt sutfoxidc

inhibttoi,.. and uittOnwlic.. In 1.. Philadclphia. h.ippincolt Williams & Wilkin,.. 215Cr. chap. 36.

bitiury Rh., Thumind, K.E.Tr.ua. WE.. Hanr,lai.

Chupter 21 • Hic:an,ine and Aniihi.stanai,iit' Agenz.s

Cimetidlne Drug Interactions

TABLE 21—2 Ben,

Metrnrndaeole

Sulfunyturea

Monci,inc t'entoxitylline

Tacrine Theophyftine

Cartsuna,cpinc

Phenytnin

Triunitereume

('luloruquinc

Propafcnone

Labettulol

I'rtupmunolnl

Tneydic antidepressanus Vatpruic uid

ia,,eplncs

Caffeine Calcium

channel

Lisaiime

Wariarin Quinine

Mctuprmukul

t,,I, IIc4anl,mic Couuiprr.oims.

112-auul

nuisi,. hi ()tjnmn, Ii. K.

Usual adult oral dose: Duodenal ulcer Treatment dose. 800—1.2(X) rng q.d. to q.i.d. with meals and at bedtime: ntaintcnancc dose. 4(1) mg q.d.

Benign gastric ulcer: 800—1.200mg q.d. to q.i.d. Hypersecrecory condition: 1.200—2.400 mg q.i.uJ.

Heartburn: 200 mg (2 OTC tablets) up to twice daily Usual pediatric dose: Oral. 20—40 mg (baset per kilogram of body weight q.i.d. with meals and at bedtime Dosage lomis: Tablet (200. 300. 400. 800 nig. liquid (300 mg/S niLl. injection (3(8) mgI2 and 50 mL)

Famotidine, USP. Famotidine. N-(aminosulfonyl 1-3U121(diaminomethylcnc )-amino J-4-thiazolyl Jmethyljthiol (Pepcid). which uses a thia,.ole bioisostcre of the imidazole heterocycle. is a white to pale-yellow crysalline compound that is very slightly soluble in waler and insoluble in ethanol.

N

/

I. Drug Fact,.

umud

Si. Louis. MO. locus

955. pp. 3(34—3(0.

in renal and hepatic impairment and in the elderly. Approximately 30 to 40% of a cinietidine dose is nietabohzed (Soxidation. 5-CH3 hydroxylation). and the parent drug and metabolites are eliminated primarily by renal excretion.

NIl2

721

CH2SCH2CH2NH

ability). The drug is eliminated by renal (65 to 70%) and metabolic (30 to 35%) routes. Famolidine sulfoxide is the only metabolile identified in humans. The effects of food or antacid on the hioavailability of famotidine are not clinically significant. Usual adult oral dose: Duodetial ulcer Treatment dose. 40 mg q.d. to hid, at bedtime: maintenance dose. 20 mg q.d. at bedtime Benign gastric ulcer: 40 mg q.d. Ilypersecrctory condition: 80—640 mg q.i.d.

Heartburn: 10 mg (I OTC tablet) for relief or I hour before a meal br prevention Dosage forms: Tablet (21) and 40 mg). oral suspension (40 mg/S mL). injection (It) mg/mi)

Ranitidine,

USP. Ranitidine. N-12-[ I 5-Idimethylamino )tnethyl 1-2-furanyl I methyl I thio lethyl I-N'-methyl-2nitro- 1,1 -ethenediamine (Zantac), is an aminoalkyl furan derivative with pK. values of 2.7 (side chaiti) and 8.2 (dirnethylarnino). It is a white solid. The hydrochloride salt is highly soluble in water.

C — NH2

II

— C — NHCH3 CH3

NSO2NH2

CHNO2

H3C — N FamoUdine Ranulkiune

Famotidine is a contpetitive inhibitor of histamine Fl2 reand inhibits basal and nocturnal gastric secretion as sell as secretion stimulated by food and pentaga.strin. Its rtirTcnt labeling indications are for the short-term treatment siduodenal and benign gastric ulcers. GERD. pathological conditions (e.g., Zollinger-Ellison syndame), and heartburn COTC only).

cases of gynecoinastia, increased prolactin levels, or :mpotence have been reported. even at the higher dosage used in patients with pathological hypcrsccrctory con-

ditions. Studies with famotidine in humans, in animal rnwlels. and in vitro have shown no significant interference sith the disposition of compounds metabolized by the heniicrosomal enzymes e.g.. cytochrome P.450 system). Famotidi tie is incompletely absorbed (4t) to 45% hioavail

Bioavailability of an oral dose of ranitidine is aboul 50 to 60% and is not significantly affected by the presence of tood. Sonic antacids may reduce ranitidine absorption and should not be taken within I hour of administration of the Hrblocker. The plasma half-life of the drug is 2 to 3 hours. and it is excreted along with its metabolites in the urine. Three melabolites. ranitidine N-oxide. r.nnitidine S-oxide, and desmethyl ranitidine. have been identified. Ranitidine is oniy a weak inhibitor of the hepatic cytochrome P450 mixed-function oxidase system In addition to being available in a variety of dosage forms as the hydrochloride salt. ranitidine is also available as a bismuth citrate salt for use with the macrolide antibiotic clarithromycin in treating patients with an active duodenal ulcer

722

Medici,,ai and Phannaceistiru( Che,ni,,rs

Wi).,,1,, and Girroid's i't'xtboak of

associated with H. priori infection. Eradication of H. reduces the risk of duodenal ulcer recurrence.

priori

Usual adult oral dose: Duodettal ulcer: Treatment dose. 200—3,0(X) ing q.d. to bid.; maintenance dose. 150 mg q.d. Benign gastric ulcer: 300 mg q.d. Hypcrscctvtoty condition: 300—6.0(X) mg 2 or more titnes daily Dosage forms: Tablets (ISO and 3(X) mg of HC) salt). syrap (IS mg/mL as HCI salt), injection (0.5 and 25 mg/mL as HCI salt)

These compounds were subsequently convened to sulfoxidc derivatives, which exhibited highly potent, irreversible inhi. hition of the proton pump. The beuzimidazole PPls are pmdrugs that are rapidly convened to a sulfenamide intermediate in the highly acidic environment of gastric parietal cells. The weakly basic beni.imidazole PPIs accumulate in these acidic compartments on the luminal side of the tubuvesictilar and canalicular structures of the parietal cells. The hen,.imi dazole PPls are chemically converted by acid to a sullcnumide intermediate that inhibits the proton pump via covalent interaction with cysteine residues (813 or 822) of the pump

H '/K -ATI'ase (Fig. 21-I 5).°" The acid lability of the benz

Nizatidine.

Nizatidine, N-I 2-Ill 2-L(dimethylamino) methyl 1-4-thiazolyl Imethyl ] thio jethyl J-N'-methyl-2-nitro1.1-ethenediamine (Axid). is an off-white to buff crystalline solid that is soluble in water, alcohol, and chloroform. The of the drug in water are 2.1 (side chain) and 6.8 (dimethylamino). /CH2SCH2CH2NH

C

NHCH3

CHNO2

/—\

S

imidazole PPls dictates that these drugs must be formulated as delayed-release. enteric-coated granular dosage fonns. The PPIs are more effective in the short term than the H:. blockers in healing duodenal ulcers and erosive esophagilis and can heal esophagitis resistant to treatment with the blockers." In addition, the benzimidatole PPIs have antimi-

crobial activity against H. pylon and thus possess efficacy in treating gastric ulcers or with one or more antimicrobials. in eradicating infection by this organism. Four henaitnidazole PPIs are currently approved for marketing in the United States (Table 2 1-3). Adverse effect profiles of the varinus PPls are difficult to compare because comparative clinical

trials do not usually include sufficient individuals to altos reliable conclusions. Relatively early in its marketing. the use of omeprazole was associated with the occurrence of H3C N

NIzatkline

CH3

Nizatidine has excellent oral bioavailahility (>90%). The effects of antacids or food on its bioavailability are not clinically significant. The elimination half-life is I to 2 hours. It is excreted primarily in the urine (90%) and mostly u.s unchanged drug 60%). Metubolites include nizatidine sulfoxide (6%), N-desmethylnizatidine (7%). and nizatidine

oxide (dimethylaminomcthyl function). Nizatidine has no demonstrable antiandrogenic action or inhibitory effects on cytochrorne P-450-linked drug-metabolizing enzyme system. Usual adult oral dose: Duodenal ulcer: Treatment dose. 300 mg q.d. to bid.; tnainte,Iance dose. ISO mg q.d. Hypersecretory condition: ISO mg hid. Dosage forms: Capsules (ISO and 30(1 mgI

Other Antlulcer Therapies PROTON PUMP INHIBITORS

The final step in acid secretion in the parietal cell is the extrusion ("pumping") of protons. The membrane pump, an H '1K -ATPase. catalyzes the exchange of hydrogen

diarrhea, headache, and rashes: longer-term experience sag. gests. however, that these adverse responses are rare. Simi

larly, characterization of adverse reaction profiles of other PPIs must await more extensive use in patients. The PPls are eliminated almost entirely by rapid

lisnu to inactive or less active metabolites (Fig. Virtually no unchanged drug is excreted in the urine and feces. The cytochrome P-45() enzyme system is primarily

involved in PPI metabolism and can be the soan:e o( drug—drug interactions for the PPIs. Inhibition of oxidaihc metabolism by omeprazole (but not csomeprazole) is respon. sible prolonging the clearance of benzodiazepines. phc• nytoin, and warfarin. Lansoprazole decreases theophyllme concentration slightly and may decrease the efficacy of oaf contraceptives. Pantoprazole and rabcprazole appear to he

free of these interactions. Further, the profound and tong. lasting inhibition of gastric acid secretion by the PPls may interfere with the bioavailability of drugs when gastric pH is an important determinant, such as the azole antifungals (e.g.. ketoconazole). ampicillin. iron salts. digoxin. and cya. nocobalamin.

Omeprazole.

Omeprazole. 5-methoxy-2.((4-tnclhosy 3.5-dimethyl- 2-pyridinyl )methyl )sulfinyl )- IH-ben7imid.t zole (Losee). is a white to off-white crystalline powder wiih very slight solubility in water. Omeprazole is an amphoteric compound (pyridine N. pK, 4.13; bcnzimidazole N-H. 1.68). and consistent with the proposed mechanism of anise

ions for potassium ions. Inhibition of this proton pump acts

of the substituted bcnzimidazoles, it is acid labile. Hence

beyond the site of action of second me.ssengers (e.g.. Caa and cAMP) and is independent of the action of secretogogues histamine. gastrin, and acetylcholine. Thus, acid pump inhibitors block basal and stimulated secretion.

the omeprazole product is formulated as

In 1972. a group of Swedish tuedicinal chemists discovered that certain pyridylmethyl bcnzimidazole sullides were

active prototi pump H '1K -ATPase inhibitors (PPIs)."

capsules containing enteric-coated granules. The absoler bioavailability of orally administered otneprazole is 301 40% related to substantial first-pass biotransformation. 'liv drug has a plasma half-life of about I hour. Most of an oral dose of omeprazole is excreted in the urine as ntetaholitcs with insignificant antisecretory activity. The pi

Chapter 21 • llLuw,nine and A,ztihistwnink Agents

A5

723

A5

H (slow)

- H20 + H20

S

NH NH A4 -

— SN A5

S—

S

Figure 21—15 U Mechanism of action of PPIs

TABLE 21-3 Proton Pu mp inhibitors M arketed In the Un ited States indication ulcer OuDdemli ulcer/If.

Omeprazole

Lansoprazoie

/ I I I

/ I I I I I

I

Pantoprazole Sodium

Rabeprazole Sodium

I I

/ I I I

Esomeprazola

Magnesium

I I I

724

WiLson and Giss'old'.c Textbook of Organic Medicinal and Pharmareu,ical chemistry

(Ol when R4 = H

CYP2CI9 HO A2

N

N

H HOI-12C

CYP2C19

0

—S——— and —S——— 0 Sulfone

Sullide

Figure 21—16 • Metabohc transformations of benzimidazole PPIs.

mary metabolites of omeprazole are 5-hydroxymeprazole (cytochrome P-450 [CYPI isozyme 2C19) and omeprazole sulfone (CYP 3A4). The antisecretory actions of omeprazole persist for 24(072 hours, tong after the drug has disappeared from plasma, which is consistent with its suggested mecha-

nisin of action involving irreversible inhibition of the proton pump H + /K + -ATPase.59 OCH3

sium trihydrate (Nexium). is the S enantiomer of omepetzole. The benzimidazole PPIs contain a chiral sulfur atom that forms an enantiomeric pair that is stable and insolsbk under standard conditions. The S isomer of omeprazoic slightly greater PPI activity, and its intrinsic clearance is approximately 3 times lower than that of R omeprazole (15 versus 43 The lower clearance of is related to slower metabolic clearance by the CYP 2CH isozyme. Although R-omeprazole is primarily transfonnrd to the 5-hydroxy metabolite. the S isomer is metabolized by

0-demethylation and sulfoxidation. which contribute little to intrinsic clearance. Usual adult dose: Erosive esophagitis: Healing dose: 20 or 40 rng q.d. for 44 weeks; maintenance dose: 20 mg q.d. Treatment of GERD: 20 mg q.d. for 4 weeks; H. pylon eradication: 40 mg q.d. for 10 days in combinatics

with amoxicillin (I g bid. for 10 days) and (500 mg bid. for 10 days)

Omeprazole

Omeprazole is approved for the treatment and reduction of risk of recurrence of duodenal ulcer, GERD. gastric ulcer. and pathological hypersecretory conditions. Usual adult dose: Oral. 20 mg q.d. Dosage form: Delayed-release capsules containing 20 mg of omeprazole in enteric-coated gninulcs

Esomeprazoie Magnesium.

Esomeprazole

magne-

sium, S-bis(5-melhoxy-2-I(S)-[(4-methoxy-3,5-dimethyl-2pyridinyl)methyljsulfinytl-IH-benzimidazole- 1-yl) magne-

Dosage form: Oral: Delayed-release capsules. 20 or 40 mg of esomepraai: (present as 22.3 mg or 44,5 mg esomcprazole ntageesiurn trihydratc) as cnteric-coatcd pellets

Lansoprazole.

Lansoprazole. 2-Il 13-methyl.4-(2.Z1 tritluomethoxy )-2-pyridyll methyl ]sulflnyl )benzimidazok (Prevacid), is a white to brownish-white, odorless crystallme powder that is practically insoluble in water. Lansoprazole is a weak base (pyridine N, 4.01) and a weak acid lbenz• imidazote N-H. pK, 1.48). Like omeprazolc, lansoprazoleit

Chapter 21 a Hi.csan,ine and Antjlsista,njnic Agsnts

725

r e

J

Esomeprazole Magnesium

essentially a prodrug that, in the acidic biophase of the panetal cell, forms an active metabolite that irreversibly interacts with the target ATPase of the pump. Lansoprazole must be formulated as encapsulated enteric-coated granules for oral administration to protect the drug from the acidic environment of the stomach. 0C113

Lansoprazole

In the fasting state, about 80% of a dose of lansoprazole (versus --50% of omeprazole) reaches the systemic circulation, where it is 97% bound to plasma proteins. The drug is metabolized in the liver (sulfone and hydroxy metabolites)

and excreted in bile and unne, with a plasma half-life of about 1.5 hours.W Usual adult door: Daily oral dose administercd before breakfast Duodenul 15 mg once daily

Erosive esophagitis: 30 mg Zollinger-Ellison syndrome: 60 mg NSAID-induced gastric ulcers: treatment and prevention Dosage fonn: Delayed-release capsules containing IS and 30 mg of lansoprazole in enteric-coated granules

Pantoprazole Sodium.

The active ingredient in Pro-

tonix (pantoprazole sodium) is a substituted henzimidazole. sodium 5-(difluoromethoxy)-2-fl(3.4-dimethoxy-2-pyridinyl)methyljsulfinylj- I H-benzimidazole sesquihydrate (1.5 H20). a compound with a molecular weight of 432.4. The benzimidazoles have weakly basic (pyridine N. 3.96) and acidic (benzimidazole N-I-I, 0.89) properties, which facilitate their formulation as salts of alkaline materials (Fig. 2 1-17). Pantoprazole sodium .sesquihydratc is a white to offwhite crystalline powder and is racemic. Pantoprazole sodium sesquihydrate is freely soluble in water, very slightly soluble in phosphate buffer at pH 7.4. and practically insoluble in n-hexane. The stability of the compound in aqueous solution is pH dependent: the rate of degradation increases with decreasing pH. At ambient temperature, the degradation half-life is approximately 2.8 hours at pH 5.0 and approximately 220 hours at pH 7.8. The absorption of pantoprazole is rapid (Cmi. of 2.5 mL, —2.5 hours) after single or multiple oral 40-mg doses. Pantoprazole is well absorbed (—77% bioavailahility). Administration of pantoprazole with food may delay its absorption but does not alter its bioavailability. Pantoprazole

R4

A4

N

RO

RO

N S

0

N

S

+ H30' H N

Figure 21—17 • Ionization of benzimidazole PPIs.

II 0

ê

726

Wilson anal Gi.s told's Te.r:book of Organic Medicinal and Plwrmaceu:ical Chemistry

is distributed mainly in extracellular fluid. The serum protein binding of pantoprazole is about primarily to albumin. Pantopr4l.ole is extensively metabolized in the liver through

the CYP system, including 0-demethylulion (CYP 2C19). with subsequent sulfation. Other metabolic pathways include sulfur oxidation by CYP 3A4. There is no evidence that any of the pantoprazole melaholites have significant pharmaco-

logical activity. Approximately 71% of a dose of pantopruzoic is excreted in the urine, with I 8% excreted in the feces through biliary excretion.

bound to human plasma proteins. Rabeprazole is extensively

metabolized in the liver. The thioether and sulfone are the primary metabolites measured in human plasma resulting from CYP 3A oxidation. Additionally, desmethyl rabepra. zole is formed via the action of CYP 2C 19. Approximately 90% of the drug is eliminated in the urine, primarily as thi' oether carboxylic acid and its glucuronide and mercaplunc

OCHa

OCH3

o

Rabeprazole sodium is formulated as enleric-coated. delayed-release tablets to allow the drug to pass through the stomach relatively intact. After oral administration of 20 mg. peak plasma concentrations occur over a range of 2.0 to 5.0 hours Absolute bioavailability for a 20-mg oral tablet of rabeprazole (versus IV administration) is ap. proximately 52%. The plasma half-life of rabeprazole ranges from I to 2 hours. The effects of food on the absorption of rabeprazole have not been evaluated. Rabcprazolc is

Na

acid mnetabolites. The remainder of the dose is recovered in

the feces. Total recovery of radioactivity was

N

No

unchanged rabeprazole was recovered in the urine or feces Usual adult dose: Oral. 20 nig once daily (duodenal ulcer forJ weeks; erosive or ulcerative GERD for 4—8 weeks): guclri OCHF2

Pantoprazoto Sodium

hypersecretory disorders. 60 mg once daily titrated to maximum of 120 mg/day Dosage form: 20-mg delayed release tablets of the sodium salt

CHEMICAL COMPLEXATION

Usual adult dose:

Erosive esophagitis associated with GERD: 40 mg q.d. for wecks: if not healed after 8 weeks of treatment, an additional 8-week course may he considered Long-temi treatment of erosive esophagitis and GERD: IV treatment of erosive esophagitir. as an alternative to cumintied oral therapy. 4t) mg q.d. by infusion for 7-. 10 days Shun-term treatment (7 to 10 days) of GERI) Treatment of pathological hypersecretory conditions associated with Zollinger.Ellison syndrome Dosage form: Protonix: Delayed-release tablet tbr oral administration: each tablet contains 45.1 mg of pantoprazole sodium sesquihydr,ule (equivalent to 40 mg pantoprazole) Protonix IV.: Frecze.dried powder fur injection equivalent to 40 mg pantoprazole/vial

Rabeprazole Sodium. Rabeprazole sodium. 2-ti 14-(3mcthoxypropoxy)-3-methyl-2-pyridinyl irnethyl isultinyll- I H-benzitnidazole sodium salt (Aciphex). is a substituted benzimidazole with a molecular weight of 381.43. Rabcprazole sodium is a white to slightly yellowish-white solid, It is very soluble in water and methanol, freely soluble in ethanol. chloroliwm. and ethyl acetate, and insoluble in ether and ahexane. Rabeprazolc is a weak base (pyridine N. pKa 4.90) and a weak acid (benzimidazole N-H. pK. 1.60).

The sulfate esters and sulfonate derivatives of polysuecha. rides and lignin form chemical complexes with the enzyre pepsin. These complexes have no proteolytic activity. Be. cause polysulfates and polysulfonanes are poorly absorbed from the 01 tract, specific chemical coniplexation appears to be a desirable mechanism of pepsin inhibition. Unions nately. these polymers are also potent anticoagulants. The properties of chemical complexanion and anticoagu. lant action are separable by structural variation. In acoinpar. ison of selected sulfated saccharides of increasing nuniber of monosaccharide units, from disaccharides through starch

derived polysaccharides of differing molecular size. thrce conclusions are supported by the data: (a) the anticoagulant activity of sulfated saccharide is positively related to molec. ular size. (b) anticoagulant activity is absent in the disaeda• rides, and (c) the inhibition of pepsin activity and the protec.

tion against experimentally induced ulceration depend ni the degree of sulfation and non on molecular size. The readily available disaccharide sucrose has been used

to develop a useful antiulcer agent. sucralfate.

Sucralfate. Sucralfate. 3.4.5.6-tetra-(polyhydroxyalu minum).a.o-glucopyranosyl sulfate-2.3.4.5-tetra-(polyh). sulfate (Carafate). is

the aluminum hydroxide complex of the octasulfame ester 01

sucrose. It is practically insoluble in water and soluble in strong acids and bases. It has a

value between 0.43 and

1.19.

Sucralfate is minimally absorbed from the 01 tract and thus exerts its antiulcer effect through local rather than sy' temic action. It has negligible acid-neutralizing or buflerine capacity in therapeutic doses. Rabeprazole Sodium

Its mechanism of action has not been c.stablished. Studies

suggest that sucralfate hinds preferentially to the ulcer sitc

Chapter 21 • 1-lisrainine and Antil,isia,ninic

727

to form a protective barrier that prevents exposure of the lesion to acid and pepsin. In addition, it adsorbs pepsin and

protective actions are proposed to be related to increases in Cl niucus and bicarbonate secretion, increases in mucosal

bile salts. Either would be very desirable modes of action.

blood flow, and/or prevention of back diffusion of into the gastric

CH2OR

H

I

0 ( OR

IAJ(OH)al,

RO

1L_OR RO

(x—øtolOandy

-

-

22to31)

I

OR

OR L

R

SO3AI(OH)2

The product labeling states that the simultaneous adminisuntion of sucraltine may reduce the bioavailahility of certain agents (e.g.. tetracycline. phenytoin. digoxin, or cimetidine). It further recommends restoration of hioavailability by separating administration of these agents from that of sucralfate try 2 hours. Presumably. sucralfate hinds these agents in the GI tract.

The most frequently reported adverse reaction to sucralfate is constipation (2.2%). Antacids may be prescribed as but should not be taken within one-half hour before or after sucralfate. Usual adult dose: Oral. I g q.i.d. on an empty stuniach Dosage form: l-g sueralilite tablets

HO

OH Mtsoprostot

Misoprostol is rapidly absorbed following oral administration and undergoes rapid deesterification to the pharmaco-

logically active free acid with a terminal half-life of 20 to 40 minutes."2 Misoprostol is commonly used to prevent NSAID-induced gastric ulcers in patients at high risk of complications from a gastric ulcer, such as elderly patients and

patients with a history of ulcer. Misoprostol has also been used in treating duodenal ulcers unresponsive to histamine H2 antagonists; the drug does not prevent duodenal ulcers. however, in patients taking NSAIDS. Misoprostol can cause miscarriage, often associated with potentially dangerous bleeding.

PROSTAGLANDINS

The prostaglandins are endogenous 20-carbon unsaturated fatty acids biosynthctically derived from arachidonic acid. These bioactive substances and their synthetic derivatives race been of considerable research and development interest as potential therapeutic agents because of their widespread physiological and pharmacological actions on the cardiovascular system. 01 smooth muscle, the reproductive system. nervous system. platelets. kidney. the eye. etc." Prosta-

glandiuts of the E. F. and I series arc found in significant concentrations throughout the Cl tract. The Cl actions of he prostaglandins include inhibition of basal and stimulated gastric acid and pepsin secretion in addition to prevention of ulecrogen or irritant-induced gross mucosal lesions of the stomach and intestine (termed cyluproIec:ion). The prostaglandins can both stimulate (PGFs) and inhibit (PCIEs and intestinal smooth musclc contractility and accumulanon of fluid and electrolytes in the gut lumen (PGEs). Theraçeulic application of the natural prostaglandins in the treatwent of Cl disorders is hindered by their lack of pharmacological selectivity coupled with a less-than-optinial biodisposition profile. Misoprostol. Misoprostol. (± )-methyl II 16-dihyJroxy-16-methyl.9-oxoprost- I 3E-en- I -oate. is a semisynderivative of POE1 that derives some pharmacological

selectivity as well as enhanced biostability from its 16Misoprostol exhibits methyl, I 6-hydroxy structural antisecretory and cytoprotectant effects characteristic of the natural prostaglandins and has a therapeutically acceptable hiodisposition profile. Although the antisecretory effects of misoprostol arc thought to be related to its agonisactions at parietal cell prostaglandin receptors, its cyto-

Usual adult dose: Or,i1. 200 Dosage form: 100- and

q.i.d. with food tablets

HISTAMINE H3-RECEPTOR LIGANDS63,M Histamine receptors are members of the G-protein—coupled receptor family involved in the regulation of neurotransmitter release in both central and peripheral neurons. The receptor encodes a 445cDNA for the human histamine amino acid protein that. when recombinantly expressed. couples to inhibition of adenylate cyclase. presumably through

Gal. The histamine Hrreceptor mRNA is highly expressed in central nervous tissues. Histamine H3 heteroreceptors have been identified in stomach, lung, and cardiac tissues receptors have been implicated of animals. Presynaptic in regulating neurotransmiuer release from histaminergic. noradrenergic. dopaminergic. cholinergic. semloninergic. and peptidergic neurons. The potential therapeutic roles of histamine H1-receptor antagonists in the CNS have been evaluated in models of learning and memory impairment. attention-deficit hyperactivity disorder, obesity, and epilepsy. Studies of the regulation of inflammatory processes. gastroprotection. and cardiovascular function suggest several therapeutic possibilities for peripherally acting histamine Hrreceptor agonists. As yet. no histamine H3-recep!or ligands have been approved for marketing in the United States.

Potent H3 agonists (Fig. 21-18) are obtained by simple modifications of the histamine molecule. The imidazole ring is a common structural feature in almost all El3 agonists. Methylation of the aminoethyl side chain of histamine favors

728

Wilson

and

Textbook of Organic

and Pl:ar,naeewical (hesnA fry

HN

N

NH2

H3C

H3C

K R-a-Methylhlstamine

Azomethine derivative ot

HN

HN NH

Sc NH2

Immepip

meld

Figure 21—18 . Histamine H3-receptor agonists.

NH S

II

HN N

—C—NH

Clobenprobil

Thioperamide

HO Cl

N

HN

(CH2)2 — during pregnancy, they should he limited to small areas .1

sorbed.

Thetapeutk Uses of Adrenal The adrenocortical steroids are used primarily for their glucocorticoid effects, including immunosuppression. anti-inflarnnnatory activity, and antiallergic activity. The mineralocorticoids are used only for treatment of Addison's disease. Addison's disease is caused by chronic adrenocortical insufficiency and may he due to either adrenal or anterior pituitary failure. The glucocorticoids are also used in the treatment of congenital adrenal hyperplasias. The symploms of Addison's disease illustrate the great importance of the adrenocortical steroids in the body and. especially, the importance of aldosterone. These symptoms include increased loss of body sodium. dccrea.sed loss of potassium. hypoglycemia, weight loss. hypotension. weakness. increased sensitivity to insulin, and decreased lipolysis. Hydroconisone is also used during postoperative recovery after surgery for Cushing's syndrome—excessive adrenal secretion of glucocorticoids. Cushing's syndrome can be caused by bilateral adrenal hyperplasia or adrenal tumors and is treated by surgical removal of the tumors or resection of hypcrpiastic adrenal gland(s). The use of glucocorticoids during recovery from surgery for Cushing's syndrome illustrates a most important principie of glucocorticoid therapy: abrupt withdrawal of glucocorticoids may result in adrenal insufficiency, showing clinical symptoms similar to those of Addison's disease. For that reason, patients who have been on long-term glucocornicoid therapy must have the dose reduced gradually. Furthermore. prolonged treatment with glucocorticoids can cause adrenal suppression, especially during times of stress. The symptoms are similar to those of Cushing's syndrome, such as rounding of the face, hypertension, edema. hypokalemia, thinning of the skin. osteoporosis, diabetes, and even subeapsular cataracts.

The glucocorticoids are used in the treatment of collagen vascular diseases, including rheumatoid arthritis and disseminated lupus crythemalosus. Although there is usually

prompt remission of redness, swelling, and tenderness by the glucocorticoids in rheumatoid arthritis, continued longterm use may lead to serious systemic forms of collagen disease, As a result, the glucocorticoids should be used infre-

quently in rheumatoid arthritis. The glucocorticoids are used extensively topically, orally, and parenterally to treat inflammatory conditions. They also usually relieve the discomforting symptoms of many allergic

conditions—intractable hay fever, exfoliative dermatitis. generalized eczema, and others. The glucocortieoid.s are also

ulcer (in which the steroids may cause hemorrhage), (b) heal

disease. (c) infections (the glucocorticoids suppress thc

intact skin and used for a limited time.

Mhse,alocortkold and Glucocorticold Produds The corticosteroids used in commercial products are shown in Figures 23-30. 23-31, and 23-32. The structures the usual changes (see Fig. 23-6) made to modify solubilit) of the products and, therefore, their therapeutic uses. In particular, the 21 -hydroxyl can be converted loan ester to makc it less water soluble to modify absorption or to a phosphate ester salt or hemisuccinate ester salt to make it more waten soluble and appropriate for intravenous use. The pmduvLc also reflect the structure—activity relationship changes dis

cussed above to increase anti-inflammatory activity or tency or decrease salt retention. Again, patients who have been on long-term glucocorticoid therapy must have the dose reduced gradually. This "critical rule" and indications are discussed above under the heading. Therapeutic Uses of Adrenal Cortex Honnones

Dosage schedules and gradual dosage reduction can be quite complex and specific for each indication. Many of the glucocorticoids are available in topical dos' age forms, including creams, ointments, aerosols, lotion. and solutions. They are usually applied 3 to 4 times a to well-cleaned areas of affected skin. Ointments are usualh prescribed for dry, scaly dennatoses. Lotions are well suite.i for weeping dermatoses. Creams are of general use for man) other dermatoses. When applied to very large areas olskrn or to damaged areas of skin, significant systemic absorption can occur. The use of an occlusive dressing can also greati) increase systemic absorption. The glucocorticoids that are mainly used for inflammation

of the eye are shown in Figure 23-31. These compounds differ structurally from other glucoconicoids. in that the 21.

Chapter 23 • Steroid Hor,rn,,ws and !l,eraj,eui teal/v Related ('an,iwunuts

811

CH3

Fluorometholone

Medrysone

0

CH3

HO

H3C

0

IHIH Figure 23—31

•

hydroxyl is missing from medrysane. fluorometholone. and nmexolone. while loteprednol etabonate has a modified ester utCI7 that leads to rapid degradation upon systemic absorption.

MINERALOCORTICOIDS

Fludrocortisone Acetate, USP.

Fludrocortisone ace21 -acetyloxy-9-lluoro- I lfl.l 7-dihydroxypregn4-ene3.20-diane. 9r -fluorohydrocortisone (Florinef Acetate), is used only for the treatment of Addison's disease and for ute,

inhibition

Loteprednol Etabonate

Ophthalmic glucocortucoids.

of endogenous adrenocortical secretions. As

shown in Table 23-8. it has up to about 800 times the miner-

alocorticoid activity of hydrocorlisone and about II Limes the glucocorticoid activity. Its potent activity stimulated the smthesis and study of Ihe many fluorinated steroids shown in Figure 23-30. Although its great salt-retaining activity

Cortisone Acetate, USP. Cortisone acetate. 21 -(acetyloxy)- I 7-hydroxypregn-4-ene-3. II .20-trione. is the 21acetate of naturally occurring cortisone with good systemic anti-inflammatory activity and low-to-moderate salt-retention activity after its in vivo conversion to hydrocontisone acetate, This conversion is mediated by Ii dehydrogenase. It is used for the entire spectrum of uses discussed above under the heading. Therapeutic Uses of Adrenal Cortex Hormones—collagen diseases. Addison's disease. severe shock, allergic conditions.chronic lymphocytic leukemia, and many other indications. Cortisone acetate is

relatively ineffective topically, mainly because it must be reduced in viva to hydrocortisone. Its plasma half-life is only about 30 minutes. compared with 90 minutes to 3 hours for hydrocortisone.

Prednisolone, liSP.

Prednisolone. .i'-hydrocortisone.

limits its usc 10 Addison's disease, it has sufficient glucocorucoid activity that in some cases of the disease, additional ducocarlicoids need not be prescribed.

17.21 -trihydroxypregna- I .4-dicne-3.20-dione. has less salt-retention activity than hydrocortisone (see Table 23-8), but some patients have more frequently experienced complications such as gastric irritation and peptic ulcers. Because

GLUCOCORTICOIDS WITH MODERATE-TO-LOW SALT

of low mineralocorticoid activity, it cannot be used alone

RETENTION

for adrenal insufficiency. Prednisolonc is available in a variety of salts and esters to maximize its therapeutic utility (see Fig. 23-30):

llydrocortisone. 11$. 17.21 -tnis the primary natural gluin humans, Despite the large number of synthetic niucocoilicoids, hydrocortisonc. its esters, and its salts rcmain a mainstay of modern adrenocortical steroid therapy nod the standard for comparison of all other glucocorticoids nod mineralocorticoids (see Table 23-8). It is used for all Hydrocortisone. USP.

II

Prcdnisolone acetate, LISP 121 -acetate) Prednisolonc sodium phosphate. USP (21-sodium phosphate) Prednisolone sodium succinate, LISP 421-sodium succinatc) Prednisolone tcbatatc, LISP (21 -tebutate)

the indications mentioned above. Its esters and salts illustrate he principles of chemical modification to modify pharmaco-

17.21 -dihyPrednisone, liSP. Prednisone. droxypregnu-l.4-dicne-3,ll,20-trione. has systemic activity

kinetic use shown in Figure 23-6. The commercially available sails and esters (see Fig. 23-30) include

very similar to that of prednisolone. and because of its lower

Ilydmcortisonc acetate, LISP (21 -acetate) Hydnucortisonc huteprute. Lisp (I 7-hutyrute. 21 -prupionatct Hydrocortisone hutyrate, LISP (I 7-hutyrate) Hydrucortisane cypionale. LiSP (21 -cypionate) Hydrucortisone sodium phosphate. USP 121 -sodium phosphate) sodium succinate. LISP (21-sodium succinate) Hydrocoruisone valcrute, liSP (I 7-vulerate)

salt-retention activity, it is often preferred over cortisone or hydrocortisone. Prednisone must be reduced in vivo to prednisolone to provide the active glucocorticoid. GLUCOCORTICOIDS WITH VERY LITTLE OR NO SALT RETENTION

Moot of the key differences bctwecn the many glucocorticoids with minimal salt retention (see Fig. 23-30) have been

812

and Gist'old's Th'xihook of Organic Medicinal and Pham,aeeutieal Chemistry

summarized in Tables 23-7 and 23-8. The tremendous therapeutic and, therefore, commercial importance of these drugs has stimulated the proliferation of new compounds and their

Desoximetasone. liSP.

products. Many compound.s also are available as salts or esters to give the complete range of therapeutic flexibility illustrated in Figure 23-30. When additional pertinent information is available, it is given below. The systemic name for each drug is provided after the common name.

structure.

Alclometasone Dipropionate, liSP.

Aiclometasone dipropionate. 7u-chloro- I lfl-hydroxy- 16a-methyl- 17,21 his( I -oxopropoxy )-pregna- I .4-diene-3.20-dione (Aclovate).

is one of the few commercially used glucocorticoids that bears a halogen substituent in the 7a position.

Amcinonide, USP. Amcinonide. 2l-(aceryloxy)-16a. 17 -Icyclopcntylidcnehis(oxy)t-9-fluoro- II fi-hydroxypreg. na-I .4-sliene-3.20-dione (Cyclocort).

Bedomethasone Dipropionate, USP.

l3eclomethadipropionnie, 9-chloro- II 17,21 -bis( I -oxopropoxy)-pregna- I .4-diene-3.20-dione (Beconase. Vancenase, Vanceril, QVAR). is used in nasal sprays and aerosol formulations to treat allergic rhinitis and asthma (see section below). sone

Betamethasone, USP.

Betamethasone. 9-fluoro- Ilfl.

17,2 1-trihydroxy- I 6fl-methylpregna- I .4-dicne-3.20-dione. is available as a variety of ester derivatives.

Desoximetasone, 9-fluoro-I

21 -dihydroxy- I 6a-methylpregna- I .4-diene-3.20-dione. like

clocortolone pivalate. lucks a C17a hydroxyl group in its

Dexamethasone, liSP.

Dexamethasone. 9-fluoro-l 17.21 -trihydroxy- I 6a-methylpregna- I .4-diene-3,20-dione. is the 16a isomer of betamethasone. Desaniethasone acetate. liSP (21 -acetate) Dexamethusune sodium phosphate. liSP (21-sodium phospltata

Diflorasone Diacetate, liSP.

Diflorasone diacetate, 17,

21 -bis(acetyloxy)-6a.9-difluoro- II fi-hydroxy- I 6a-mcthylpregna- I .4-diene-3.20-dionc.

Flunisolide, liSP.

Flunisolide. 6a-fluoro- II $.2 I-dittydroxy- I 6a. 17-1(1 -methylethylidene)his( oxy) Ipregna. 1.4dicne-3.20-dione. (See following section for use of flunisol. ide in the treatment of asthma.)

Fluocinolone Acetonide, liSP.

Fluocinolone acelonide, 6a.9-dilluoro- II $.2 I -dihydroxy- 16a, 17-1(1 -methylcthylidenc)bis(oxy)Jpregna-I.4.diene-3.20-dione. also knosa as 6a-fluorntriumcinolone acetonide. is the 21-acetate deriv-

ative of Iluocinolone acetonide and is about 5 times mote potent than fluocinolone acetonide in at least one topical activity assay.

Retamethasone valerate, USP (l7-valcratc) I3etametha.sone acetate, USP (21-acetate) Bctamethasone sodium phosphate. liSP (21-sodium phosphate) Hetamethasone dipropionate. liSP I 7-propionatc. 21-propionate)

Budesonide, USP.

Budcsonidc. I 6a. I 7-Ibutylidenebis(oxy )I- I Ifl.21 -dihydroxypregna- I ,4-dienc-3,20-dione (Entocort). in oral capsules is used to treat Cmhn's disease. The

affinity for the GR is approximately 200-fold greater than that of hydrocorlisone and 15-fold greater than that of prednisolone. Budesonide is a mixture of epinters, with the 22R form having twice the affinity for the GR of the S epimer. This glucocorticoid is metabolized by CYP 3A4. and its levels can be increased in the presence of potent CYP 3A4 inhibitors. Budesonide is also used in an inhaled formulation for the treatment of asthma (see below).

Clobetasol Propionate, liSP.

Clobetasol propionate. 2 l-chloro-9-tluoro-I I 6f3-methyl- I 7-( I -oxopropoxy-pregna- I .4-diene-3.20-dione (Temovate).

Ckx:oriolone pivalate, 9Clocortolone Pivalate,, liSP. chloro-2 I -(2.2-dimethyl- I -oxopropoxy)-6a-fluoro- II

Fluorometholone, liSP.

Fluorometholonc. 94luoro11$. l7-dihydroxy-6a-methylpregn-4-cne-3.20-dione(FluteOp. FML). lacks the typical C21 hydroxyl group of ticoids and is used exclusively in ophthalmic products. Thc 17-acetate of Iluorometholone is also used as an suspension (Flarex).

Flurandrenolide,

liSP. Aurundrcnolide. 6a-fluornII $.2 I -dihydroxy- 16 a, I 7-[( I -methylethylidene)bis(oxy;Jpregn-4-ene-3.20-dione. although available as a tape peed uct. can stick to and remove damaged skin, so it should k

avoided with vesicular or weeping dermatoses.

Fluticasone Propionate, liSP.

Fluticasone propionaic.

S-(fluoromethyl)

6a.9-dilluoro- II f3-hydroxy- I 6a.methyl. 3-oxo- I 7a-( I -oxopropoxy)androsla- I .4-diene- I oatc (Cutivate). is 3- to 5-IbId more potent than sone in receptor binding assays. (See also the

tion on inhaled corticosteroids.)

Haidnonide.

droxy- I 6a-methylpregna- I .4-diene-3.20-dione (Cloderm), along with desoximetasone. lacks the C17a oxygen functionality that is present in other glucocorticoids but still retains good glucocorticoid activity.

Halcinonide. 21 -chloro-9-Iluoro- I Ifl.hy droxy- I 6a. 17-1(1 -methylethylidenebis(oxy)Ipregn-4. etc 3.20-dione. was, the first chioroglucocorticoid marketed Like many of the other potent glucocorticoids. it is used topically.

Desonide, lisP.

Halobetasol Propionate, lisP.

Desonide. I l$-2 l-dihydroxy-l6a.171(1 -mcthylethylidcne)bis(oxy)tpregna- I ,4-diene-3,20-dione (DesOwen, Tridesiol).

Halobetasol propkxi

ate. 21 -chloro-6a.9.ditluoro- II $-hydroxy- 16$-methyl -17 (I -oxopropoxy)pregna- I .4-diene-3.20-dione.

Chapter 23 • Steroid Honnv.nie.c and Therapeuiieallr

Co,npountl.c

813

Loteprednol Etabonate, USP. Locprednol ctahonate. chtoromethyl I 7a-[ethoxycarhonyl )oxyI- II fl-hydroxy-3osoandrosta- 1 .4-diene- I 7-carboxylate (Aires. Lotemax). has a moditied carboxylate at the C17 position rather than the typical ketone functionality. This modification maintains affinity for the glucocorticoid receptor but allows facile metabolism to inactive metaholites. This limits the systemic

than triamcinolone. The plasma half-life is approximately

action of the drug. Loteprednol etahonate is used as an ophthalmic suspension that has greatly reduced systemic action due to rapid metabolism to the inactive carboxylate (Fig. 2331).

tionally, the acetonidc may be given by intrabursal or. sometimes. intramuscular or subcutaneous injection. A single intramuscular dose of the diacetate or acetonide may last up to 3 or 4 weeks. Plasma levels with intramuscular doses of

Medrysone. USP. Medrysone. II f3-hydroxy-6a-methylpregn-4-ene-3.20-dione. is unique among the corticoste-

the acetonide are significantly higher than with triamcinolone itself. The acetonide is also used to treat asthma and allergic rhinitis (see following section).

90 minutes. although the plasma half-life and biological halflives for glucocorlicoids do not correlate well. The hexacetonide is slowly converted to the acetonide in vivo and is given only by intra-articular injection. Only triamcinolone and the diacetate are given orally. The acetonide and diacetatc may

be given by intra-articular or inirasynovial injection; addi-

roids. in that it lacks the usual lla,2l-diol system of the others (Fig. 23-31). Currently. ii is used only for treatment of inflammation of the eyes.

INHALED CORTICOSTEROIDS FOR ASTHMA AND ALLERGIC RHINITIS

Methy!prednisolone, USP. Methyiprednisolone, Ii 7.2 I-trihydroxy-6a-methyl-l.4-pregnadiene-3.20-dione. is

The National Asthma Education and Prevention Program has provided recent recommendations on the treatment of asthma, including a strong recommendation for the first-line

asailable unmodified or as ester derivatives.

use of inhaled corticosteroids for severe and moderate persis-

Mclhylprednisolonc acetate. USP Mcthylprcdnisolone sodium succinatc. liSP

Mometasone Furo ate.

USP.

Mometasone

furoate.

9.21 -dichloro- I 7a-l(2-furanylcarbonyl)oxyj- Ii 16a-rnethylpregna-l.4-diene-3,20-dione (Elocon). isa highpotency glucocorticoid available in cream, lotion, or ointment formulations for topical use. In addition, momelasone (umate monohydrate is fonnulated in a nasal spray for treating allergic rhinitis (see following Section).

Prednicarbate. USP.

Prednicarbate.

I

- l-oxopropoxy)pregna-l ,4-diene3.20-diane. is a prednisolone derivative with a C2 I propionate ester and a C17 ethyl carbonate group. It is available for use only in a 0.1 topical cream. Prednicarbate is a mediumpotency glucocorticoid. onvl)oxy I-I

Rimexolone. II I 6a. I 7adimethyl- I 7-( I -oxopropyl )androsta- I 4-diene-3-one, like Rimexolone, USP.

tent asthma in all age groups. The corticosteroids currently used in inhaled formulations are all relatively potent topical corlicosteroids that have the advantage of rapid deactivationl inactivation for the portion of the dose that is swallowed. The development of glucocorticoids that are efficiently inactivated metabolically when swallowed has greatly reduced the systemic side effects associated with the use of steroids in asthma treatment. The older corticosteroids that are used orally (e.g.. methylprednisolone. prednisolone. and prednisone) have much greater systemic side effects, and their use should be limited, if possible. Although systemic side effects are reduced, they are not completely eliminated. The side effects can vary with the steroid used and the frequency of administration. The five glucocorticoids that are currently approved for use in the United States for asthma as inhaled fonnulations are beclometha.sone dipropionate. budesonide. tlunisolide. fluticasone propionate. and triamcinolone acetonide (Fig. 23-32). Mometasone furoate will likely be added soon for an asthma indication. Ciclesonide is the newest glucocorticoid being pursued for use in the treatment of asthma. Ciclcsonide

medrysone and fluorometholone. lacks the C2 I hydroxyl

is in phase III clinical trials and may he available in the

group. In addition. rimexolone has an additional methyl group in the 17a position. a site where a hydroxyl group

United States within a few years. Clinical trials suggest that

is typically found. Rimexolone is available as a suspension ophthalmic use (Fig. 23-31).

available inhaled steroids. The (allowing agents are also available in nasal inhalers

it may have better tolerability than some of the currently

6a.

for the treatment of allergic rhinitis. Details tire provided below for the mode of metabolic inactivation involved for each of these products. Although all of these agents have much lower systemic effects than the oral steroids, sonic

Trianicinulone acetonide, USP: Triamiicinotone-l6a,l7-acetoride Triamcinolonc hexacetonide, liSP: Triamcinolonc acctonide 21-

systemic effects, as measured by suppression of the hypothalamic—pituitary—adrenal (HPA) axis, have been observed for these products.

Triamcinolone, USP.

Triamcinolone, 9-Iluom- II

17.21 -tetrahydroxypregna- I .4—diene-3.20-dione.

I 3-(3.3-dimcthyl thutyramel

Tnamcinolone diacciate. USI': 16.2 1-Diacetate

Triamcinolnne acetonide is approximately 8 times more

GLUCOCORTICOIDS FOR ASTHMA AND ALLERGIC RHINITIS

ically applied triamcinolone acetonide is a potent anti-in-

Beclomethasone Dipropionate. Beclomethasone dipropionate (Beclovent, l3econase, Vanceril, Vancenase)

flanunatory agent (see Table 23-8). about 10 times more so

(BDP) is rapidly converted in the lungs to beclomethasone

potent than prednisone in animal inflammation models. Top-

814

Wilson

and Gin void's Textbook of Organic Medicinal and Pharmaceutical Chemistry

HO

Tnamcinolone Acetonide (Azmacort, Nasacorl)

Beclomethasone Diproptonate (Bedovent, Beconase, Vancerli, Vancanase)

H3C

Ftuticasona Proplonate (Flovent. Ftonase)

Mometasone Furoata (Nasonex)

H

Budesonide is a mixture of the two isomers (S isomer can vary from 40 to 51%) (Pulmicort, Rhinocort) Ciclesonide

Figure 23—32 • Giucocorticoids used to treat asthma and allergic rhinitis (some are also used topically)

17-monopropionate (17-BMP). the metabolite that provides the bulk of the anti-inflammatory activity. The monopropionate also has higher affinity for the GR than either the dipropionate or becloniethasone. The portion of BDP that is

swallowed is rapidly hydrolyzed to 17-BMP. 21-BMP (which arises by a transesterification reaction from 17BMP), and beclomethasone itself.'43 Beclomethasone has

humans is the I 7/3-carboxylate derivative. As expected, a charged carboxylate in place of the normal acetol functional ity at Cl 7 greatly reduces affinity for the glucocorticoid receptor (2,000-fold less than the parent), and this melabolbe is essentially inactive. The metabolite is formed via the CYP 3A4 system, so care should be taken ii liuticasonc propionate is coadministered with a CYP 3A4 inhibitor such as

much less glucocorticoid activity than the monopropio-

nazole or ritonavir. Clinically induced Cushing's

nate.'4'

has been observed when inhaled fluticasone propionate

Budesonide. Budesonide (Pulmicort Turbuhaler. Rhinocort) is extensively metabolized in the liver, with 85 to 95% of the orally absorbed drug metabolized by the first-

administered concurrently with ritonavir)4' Fluticasone is also available in an inhaled in combination with the long-acting /32-agonist salmeterol

(Advair Diskus).

pass effect. The major metabolites are

ide and 16a-hydroxyprednisolone. both with less than 1% of the activity of the parent compound. Metabolism involves the CYP 3A4 enzyme, so coadministration of budesonide with a known CYP 3A4 inhibitor should be monitored carefully.

Mometasone Furoate.

Mometasone

furoate (Na.co.

flex) undergoes extensive metabolism to multiple metabolites. No major metabolites are detectable in human plasma after oral administration, but the 6/3-hydroxy metabolite is detectable by use of human liver microsomes. This metabo

lite is formed via the CYP 3A4 pathway.

Flunisolide.

The portion of a flunisolide (AeroBid, Na-

sarel) dose that is swallowed is rapidly converted to the 6/3hydroxy metabolite after first-pass metabolism in the liver.

The 6$-hydroxy metabolite is approximately as active as hydrocortisone itself, but the small amount produced usually has limited systemic effects. Water-soluble conjugates are inactive.

The main metabolite of fluticasone propionate (Flovent. Flonase) found in circulation in

FIut!casone Propionate.

Trlamcinolone Acetonide.

The three main metabolites

of triamcinolone acetonide (Azmacort. Nasacort) are 6/J.hvdroxytriamcinolone acetonide. 21 acetonide, and 6f3-hydroxy-2 l-carboxytriamcino!onc acetonide. All are much less active than the parent compound. The 6/3-hydroxyl group and the 21 -carboxy group are both structural features that greatly reduce glucocorticoid action. The increased water solubility of these metabolitcs also tail. itates more rapid excretion.

Chapter 23 s Steroid hormones and Therapeutical!'. Related Compounds

815

2. Nonnan. A. W.. and Litwnck. G.: Hormones. 2nd ed San Diego. Academic Puts'., 1997. 3. Williams, I). A., and Lcmkc, 1. L. teds.): Foye's Principles nid Chemistry. 5th ci!. Philadelphia. Lippincolt Williams & Wilkins. 2002.

Spironolactone (Aldolactone)

4. Moss, G. P.: Eur. J. Biochcm. 186:429—458, 989. 5. Stocco. D. M.: Annu. Rev. Ptsysiol. 63:193—213. 2(8)1. 6. Lin. 0.. Sugawara. T.. Strauss. 3. F.. Ill. ci at.: Science 267: la28—1831. 1995. 7. Aranda, A., and Pascual. A.: Physiol. Rev. 81:1269—1304. 2001. 8. Cheung. J., and Smith. 0. F.: Mol. Endocnnal. 14:939-946. 2(100. 9. Pratt, W. It., and Taft, 0. 0.: Endocr. Rev. 18:306—3M). 1997. tO. DeFranco, D. B.: Mol. Endocrinol. 16:1449—1455, 2002. II. Brzozowslrj, A. M.. Pike. A. C., Dauler, Z.. ci at.: Nature 389: 753—758, 1997.

12. Tanenbaum. D. M.. Wang. Y.. Williams. S. P.. and Sigler. P. B.: Proc. Nail. Acad. Sci. U. S. A. 95:5998—6003, 1998.

13. Pike, A. C., Brzozowski, A. M., Hubbard, R. E., et al.: Emboi. 18: 4608—4618. 1998.

14. Williams, S. P.. and Sigler. P. B.: Nature 393:392—3%. 1998.

IS. Sack. i. S.. Kish. K. F.. Wang. C.. ci at.: Proc. Nat). Acad. Sci. U.S.A. 98:4904-4909, 2001. 16. Dcy. R.. Roychowdhury. P.. and Mukhctjec. C.: Protein Eng. 14: Eplerenone (lnspra)

Figure 23—33 . Aldosterone receptor antagonists.

565—571. 2001.

17. Dcy. R., and Roychowdbuty. P.: J. Biomol. Struct. Dyn. 20:21—29. 2002.

18. Ekena, K.. Katzenellenbogcn. J. A.. and Kaizenellenbogen. B. S.: J. Biol. Chem. 273:693—699. 19911.

MIn.ralocortlcld R.csptor Aatago.Ists Antagonism of the mineralocorticoid receptor can have profound effects on the renin—angiotensin system. thus having significant cardiac effects. Structurally, these compounds have an A-ring enone, essential for recognition by the receptor, but the 7a substituent and the D-nng spirolactone provide structural elements that lead to antagonism (Fig. 2333).

Spironolactone. USP. Spironolactone. 7a-(acetylthio)Ila-hydroxy-3-oxopregn-4-ene-3-one-2 I -carboxylic acid v.lactone (Aldactone), is an aldosteronc antagonist of great medical importance because of its diuretic activity. Spironolactone is discussed in Chapter 18.

19. Duax. W. L.. ci a).: Biochemical Actions of Hormones, vol II. New York. Academic Press. 984. 20. Duax. W. L., Griffin, 2. F.. Weeks, C. M.. and Wawrsak. Z.: 2. Steroid Biochem. 31:481—492, 1988. 21. Hanson, 3. R.: Nat. Prod. Rep. 19:381—389,2002. 22. Mosselman, S.. Polman. 3.. and Dijkrma. R.: FEltS Lctt. 392:49—53. 1996.

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26. Katzenellenhogen, B. S.. Sun. J.. Harnngton. W. R., ci at.

Ann.

N. Y. Acad. Sci. 949:6—IS. 21.8)1.

27. Kaizenellenbogen. B. S.. and Katscnellcnhogcn. 3. A.: Science 295: 2380—2381. 2002.

28. McDonnell. 0. P.. Connor. C. E.. Wijoysralnc. A.. et at.: Recent Prog. Horns. Re'.. 57:295—316, 2002.

Eplerenone, USP. Eplerenone, 9,11 a-epoxy- I 7a-hydroxy-3-oxopregn-4-enc-7a,2 I -dicarboxylic acid, y-Iactone, methyl ester (lnspra). is a new aldosteronc antagonist that was approved by the FDA in 2002 for the treatment of hypertension.

29. McDonnell. D. P.. and Norris, 3. D.: Science 296:1642—1644. 2002. 30. Sanchez. K.. Nguyen. 0.. Rocha. W., ci al.: Bloessays 24:244—254. 2002.

31. Gelmnnn. E. P.: 3. Clin. Oncol. 20:3001 —3015. 2002.

32. DeRijk. K. H., SchaaI. M., and de KIoct, E. K.: 2. Steroid Biochem. Mol. Biol. 81:103—122. 2002. 33. Bums. K. H.. and Matsuk. M. M.: Endocrinology 143:2823—2835, 2002.

34. Themmcn. A. P. N..and Huhianiemi. I. T.: Endocr. Rev. 21:551—583,

Acknowledgment I would like to thank Debra Peters for assistance with the illuslration of several figures. I would also like to express my appreciation to the authors of various review articles on the steroids. Without the dedication and hard work of these individuals, the assembly of this chapter would have been

2000.

35. Ruenitz, P. C.: Female sex hormones and analogs. In Wolff. M. E. (ed). Burger's Medicinal Chemistry and Drug Discovery. 5th ed. New York. John Wiley & Sons, vol. 4. 1996, pp. 553—587. 36. Rich. K. L.. Hoih. L. R.. Geoghegan. K. F.. et al.: Proc. Nail. Acad. Sci. U. S. A. 99:8562—8567. 2002. 37. Martin. C. R.: Endocrine Physiology. New York. Oxford University Press. 1985.

a much more challenging task.

38. Schuler, F. S.: Science 103:221. 1946. 39. Jordan, V. C.. Mittal. S., Garden. B.. et al.: Environ. Health Perapect

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H

C

A

P

T

E

R

w

24

—'

Prostaglandins, Leukotrienes, and

p—p

Other Eicosanoids THOMAS J. HOLMES, JR.

The prostaglandins (PCIA through PGJ) are one group of

characterization of the cicosanoid substances but also were

naturally occurring 20-carbon fatty acid derivatives pro-

the first to realize the profound significance of ihc arachi.

duced by the oxidative metabolism of 5.8.11. 14-eicosatetraenoic acid, also called arachidonic acid. Other so-called cicosanoids produced in the complex biological oxidation scheme called the arachidonic acid cascade (Figs. 24-I and 24-2) are thromboxanc (TXA2). the leukotrienes (LKTs A to F). and the highly potent antithrombotic agent prostacyclin (P012). The naming and the numbering of these 20carbon acids are included in Figures 24-I to 24-3. Although eicosanoid-derived agents in current human clinical therapy are few, the promise of future contributions from this area is presumed to be very great. This promise stems from the fact that intermediates of arachidonic acid metabolism play an es.sential modulatory role in many normal and diseaserelated cellular processes. In fact, much of the pain, fever, swelling, nausea, and vomiting associated with "illness," in general, probably results from excessive prostaglandin pmduction in damaged tissues.

donic acid cascade in disease processes, particularly inllam• mation. These individuals first proved that the mechanism of the anti-inflammatory action of aspirin and related

roidal anti-inflammatory drugs (NSAIDs) was directly due to their inhibitory effect on prostuglandin formation. It shown subsequently that the analgesic and of these NSAIDs. as well as their proutceralive and anticoae. ulant side effects, also result from their effect on eicosanaid

(e.g.. inhibition of cyclooxygenases ICOX-l and COX-21). metabolism

I

and 2

Many books have been published describing the role of eicosanoids in the inflammatory process, the immune sys. tern. carcinogenesis, the cardiovascular system, reproduclise processes, gastric ulceration, and the central nervous system (see Selected Reading). An annual update of research results in this area has been published since 1975, Advances in Pra,s• taglandins. Tl,ron,ho.ranes. and Leukotriene Research. Re.

cent research findings in this area may appear in a of biochemical and clinical journals hut are the primary conS

HISTORY OF DISCOVERY Early in the past century (1931). Kurzrok and Lich noted that human seminal fluid could increase or decrease spontaneous muscle contractions of uterine tissue under controlled condiLions.' This observed effect on uterine musculature was be-

lieved to be induced by an acidic vasoactive substance formed in the prostate gland, which was later (1936) termed

prostaglandin by von Euler.2 Much later (1950s), it was found that the acidic extract contained not one but several structurally related prostaglandin substances.3 These materials subsequently were separated, purified, and characterized as the prostaglandins (PGA through PCi), varying somewhat in degree of oxygenation and dehydrogenation and markedly

in biological activity (Table 24-I). Specific stereochemical syntheses of the prostaglandins provided access to sufficient

purified material for wide-scale biological evaluation and confirmed the structural characterization of these complex substances.4

Although many scientists have contributed to refined characterization of the eicosanoid biosynthetic pathways and the biological consequences of this cascade, the discerning and persistent pioneering effons of Sune Bergstrom, Bengt Samuellson. and John R. Vane were recognized by the award of a shared Nobel Prize in Medicine in 1982. These scientists not only dedicated themselves to the chemical and biological

818

cern of two specific journals: Prostaglandins and Other Lipid Mediators and Prostaglandins. Leuko:ricsw.s. (111(1 Es

.wntial Fairs' Acids.

EICOSANOID BIOSYNTHESIS Prostaglandins and other cicosanoids are produced by the oxidative metabolism of free arachidonic acid. Under normal circumstances, arachidonic acid is not available for memaho. lism as it is present as a conjugated component of the phos. pholipid matrix of most cellular membranes. Release of free

arachidonic acid, which subsequently tisay be metabolized, occurs by stimulation of phospholipase enzyme activity in response to some traumatic event (e.g., tissue damage, toxin exposure. or hormonal stimulation). it is believed that the clinical anti-inflammatory effect of gin. cocorticat steroids (i.e., hydrocortisone) is due to their ability to suppress PLA2 activity via lipoconins and thus prevent the release of free arachidonic acid.5 Modulation of PLA, activity by alkali metal ions, toxins, and various therapotisc agents has become a major focus of biological research cause of the change.s in cicosanoid production and the drj' matic biological effects accompanying PLA2 stimulation re suppression. Although initially it was believed that the in fiammatory response (swelling, redness, pain) was princi.

_ Chapter 24 S Pro.ciaglandin.c. Leukogrie,,e.s. and Oilier Eirosaneids

819

85C00H Asachidornc Acid

Cyctooxygenase

OOH

/4C9OH

yW

OH

—,

0 OH TXA2 (thromboxane A,)

PGH2

OH (pOStacydin)

PGF2,,

0

OH

cxRt7÷12o OH

OH PGJS

POD2

OH POE2

Figure 24—1 u Cyclooxygenase pathway

pally due to POE2. recent interest has focused on the interre-

lationships of POE-type eicosanoids with P012 and cytokines. such as interleukin- I and interleukin-2, in the modulation of intlammatory reactions.6

Two different routes for oxygenation of arachidonic acid have been defined: the cyclooxygenase pathway (Fig. 24I) and the lipoxygenase pathway (Fig. 24-2). The relative significance of each of these pathways may vary in a particuat tissue or disease state. The cyclooxygcnasc pathway, so named because of the unusual bicyclic endoperoxide (P002) produced in the first step otthe scquence. involves the highly

sicreospecific addition of two molecules of oxygen to the arachidonic acid substrate, followed by subsequent enzyme-

controlled rearrangements to produce an array of oxygenated eicosanoids with diverse biological activities (see Table 24-

I). The first enzyme in this pathway. PGH synthase. is a hemoprotein that catalyzes both the addition of oxygen (to form P002) and the subsequent reduction (peroxidase activity) of the 15-position hydroperoxide to the lS-(S)-configuration alcohol (PGH2)! PGH synthase (also called cyclooxvgenase- / /COX- 1/ or cvc/ooxvge'naxe-2 (COX-2/. and formerly PG .cvntheiase) has been the focus of intense inves-

tigation because of its key role as the lirst enzyme in the arachidonic acid cascade.5 It is this enzyme in constitutive (COX-l) or inducible (COX-2) Form that is susceptible to inhibition by NSAIDs, leading to relief of pain. lever, and

820

%tjlxon and Gis"old'.s

of Orca,,ic Medicinal and P!,arn,aceu,ieal Clw,,,ia:ri

Oa—j OOH

5HEIE

5.1-IPETE

HO H G$H t,ansie,ase

4ydro4ase

Cys'G)y

A, )LTA,)

B, (LIB,)

Leukoinene C. O.TC,)

T'wisicrai,

HO

HO H

H

HO H

HS Cys-G)y

E, LIE,)

Leuhoinone F, ILIF,)

D,

Figure 24—2 • Lipoxygenase pathway.

intlammation.6 "This enzyme is also inhibited by the w3 (omega-3) fatty acids (eicosapcntaenoic acid IEPAI and docosahexaenoic acid IDHAJ) found in certain cold-water

body temperature, central and peripheral pain and decreased vascular perfusion) based on their tissue disthbu.

fish and provided commercially as nutritional supplements. leading to beneficial cardiovascular effects)° This enzyme will metabolize 20-carbon fatty acids with one more or one less double bond than arachidonic acid, leading to prostaglandins of varied degrees of unsaturation (e.g.. PGE, or PGE3. for which the subscript number indicates the number of double bonds in the molecule). Prostaglandin H2 serves as a branch-point substrate ti,r specitic enzymes, leading to the production of the various prostaglandins. TXA2. and PCIa. Even though most tissues can produce PGH2, the relative production of each of these derived eicosanoids is highly tissue specific and may be subject to secondary modulation by a variety of cofactors. The complete characterization of enzymes involved in branches of the eyclooxygena.se pathway is currently under way. Specific cellular or tissue responses to the eicosanoids are apparently a function of available surface receptor recognition sites.' The variety of tissue responses observed on eicosanoid exposure is outlined in Table 24-I. Non—tissue-selec-

The lipoxygenase pathway of arachidonic acid nietahn. lism (Fig. 24-2) produces a variety of acyclic lipid peroxides (hydroperoxycicosatctr.tenoic acids IHPETEsD and derived

tive inhibitors of the cyclooxygenase pathway, such as aspirin, thus may exert a diversity of therapeutic effects or side effecis (e.g.. decreased uterine muscle contraction and platelet aggregation, gastric ulceration, lowering of elevated

tion.s.

alcohols (hydroxyeicosatetraenoic acids I HETasJ

Al-

though the specific biological function of each of these limoygenasc-dcrived products is not completely known, they are

believed to play a major role as chemotactic factors that promote cellular mobilization toward sites of tissue injury. In addition, the glutathione (GSH) conjugates LKT-C4 and LKT-D4 are potent. long-acting bronchoconstrictors that are released in the lungs during severe hypersensitivity episodes

(leading to their initial designation as the

'slow-reacting

substances of anaphylaxis" ISRSA5IL Because of the presumed benefit of preventing of LKTs in asthmatic patients, much research effort is being dedicated to the design and discovery of drugs that might selectively inhibit the lipoxygenase pathway of arachidonic acid metabolism without affecting the cyclooxygenase pathway.'' Zik'utnn

(Zyllo by Abbott Laboratories) specifically inhibits the Iipoxygcnase pathway, Ii has been proposed that aspirin hypersensitivity in susceptible individuals may result mmmcl

fectively "shutting down" the cyclooxygenase tt,etabulic route, allowing only the biosynthesis of lipoxygcnase path'

Chapter 24 • Prostaglandin.r. Leuknrriene.c, and Other Proslagiandins

Nonenzymatic Degradation

Enzymatic Metabolism

p-Oxidative

0

HO PGE2

P6F20

HO

HO

)

OH

HO

COOH O

0

R,7 (Unstable)

PGC7

R 13-20

O

jHeshilt

PGB2

R13_20 Thromboxane A2

OH TXB2

Prostacyclin

H20

20

Prostacyctin (PGI2)

Figure 24—3 . Elcosanoid degradation.

822

Wi/san and Gist'old'c

i4 Organic' Medicinal and Pharrnaec'u:icaI C/u'mi,sirv

Biological Activities Observed with the Eicosanolds TABLE 24—1

Observed Biological Activity

Substance

Weak inhibitor of platelet aggregation

Vactidilatitin

PGE1

Inhibitor of lipolysis Inhibitor of platelet aggregation

Stimulates contr.iclii,n of gastrointestiital sntooth muscle

Stimulates Ityporalgesk response Remit s'ascidilutution

Stimulates uterine stmtiioltm tnuwk couttr,tettun Protects gastrointestinal epitlmelia from acid degradailon

Reduces secretion of

acid

Elevates tliennoregulatimrv set point in anterior hypothalamus

PGF.

StitituLites breakdown of corpus lmmwutn

(lutcolysis) in animal' Smmnimilaics uterine smutooth muscle comttnictioum

Potent inhibitor iii platelet aggregation

PGI,

Poteni vasuidilamor

increases cAMP tevcls in Stimulates osucogenesis

PGJ,

Inhibit' cell prnlilenitiuun

TXA,

l'otcnt inducer of platelet aggregation Potent rasoconstrictiur

Decreases cAMP levels in platelets Stiuiutilatci. releitse i,f ADP and sirrotonin (mmmi platelets Increases lmtkocyte cttemott,sis and iuggregutiuun

PGH synlhase will become hydroxylated directly during arachidonic acid metabolism, in a process labeled cvaxida' This cooxidative process presumably occurs during the peroxidase conversion of PGG2 to PGH2. which duice tively makes available a nonspecific oxidizing equivalent. The cooxidation process has been implicated in the aclisa• lion of polycyclic aromatic hydrocarbons to fonu proximate carcinogens. The only group of drugs that has been thoroughly chanw• terizcd for its effect on arachidonic acid metabolism ts the NSAIDs. This large group of acidic. aromatic moleculesesens a diverse spectrum of activities (mentioned above) by inhibitioti of the first enzyme in the arachidonic acidcascadc, PGH syntha.se (also called COX-! and COX-2). Such agents as salicylic acid. phenylbutazone. naproxen. sulindac, and ibuprofen presumably act by a competitive. reversible inltihi. tion of arachidonic acid oxygenation.t7 Aspirin and ceflain halogenated arornatics (including indoniethacin. hiurbipro. fen. and Meclornen appear to inhibit PGH synthase in a time-dependettl. irreversible manner.'5 Since this irrevcoible inhibition appears critical for aspirin's significant effect on platelet aggregation and, therefore, prolongation of bleeding this discovery has led clinicians to recotuntend the daily consumption of low doses of aspirin (81 ntgl by patients at risk for myocardial infarction (Ml. heart allacki,

particularly a second Ml. Interestingly, aspirin's primary competitor in the com,ncrcial analgesic marketplace. acctaminophen. is a rather weak

inhibitor of arachidonic acid oxygenation in

This. in

Potent and prolonged cummitr.ictkun of guinea pig ileumn smooth muscle

in concert with its lack of in vitro anti-inflammatory

Increased vascular penneahihity in guinea pig skin (amugnmentcd b) POEs

(while maintaining analgesic and antipyretic activity equivalenI to that of the salicylatest has led to the proposal lh.d acetaininophen is more active inhibitor of cyckuoxy' genases in lhe brain, where peroxide levels (which stimulate cyclooxygenase activity) are lower than in inflamed periph-

Vasodilutatiumn of rut and rabbit gastric circulation

eral joituls, where lipid peroxide levels arc high." In fact

Inhibits induced platelet aggregntion

when in vitro experimental conditions are modified to the so-called peroxide tone. acetaminophen becontes as ci fective as aspirin in reducing arachidonic acid metabolism."

Aggregateshumutan tcuuliocytes Proittores leukocytc chamcna.sis

way

hepatic hydroxylation. phenolic derivatives of adttlinislercd drugs becomc readily available in vivo. Even more directly. aromatic molecules on in vitro incubation with microsomal

SIow.reaeling substances aI :unapluylaxiv

Sronclisucm,nstrictivc in hiumnitni

5-or 12-HETE

tered agelils. Because tnost aromatic drug molecules undergu

fact, is a characteristic of reversible. noncotnpelitive.phcnolic antioxidanl inhibitors itt generaL2t This determinalion,

Contracts guinea pig luttg parens'hymal strips

5- or t2-HPETIS

hoxylic acids and phenolic aaitioxidants. implies their susceptibility to influence by a variety of exogenously adminis-

intermediates,

including

the

bronchoconstrictive

LKTs.

COX-2 INHIBITORS The newer anti-inflammatory COX-2 inhibitors (e.g.. cete-

coxib. rolecoxib. and valdecoxib) arc claimed to shos greater inhibitory selectivity for the inducible fomi (if cyclooxygcnase.22 Although not absolute, this

DRUG ACTiON MEDIATED BY EICOSANOIDS The ubiquitous nature of the eicosanoid-producing enzymes

implies their significance in a variety of essential cellular processes, Additionally, the sensitivity of these enzymes to structurally varied hydrophobic materials, particularly car-

provides a potential therapeutic advantage by reducing sidc effects, particularly gastric irritation and Unfar. tunately. this altered profile of activity is not totally risk free The manufacturer of rofecoxib (Vioxx) has recently (AfmI 2002) issued a warning regarding the use of this product in patients with a medical history of ischemic heart disease

Oilier

Chapter 24 • Pros,aglandins. Leukoiric,,e.c.

COX-2 inhibitors do not share the beneficial effects of aspina in preventing cardiovascular throinbotic events.

823

with their limited distribution from this site of adniinistration.24

Iv.

DESIGN OF

is

DRUGS

The ability to capitalize successfolly on the highly potent

ii. it! C-

it.

biological elTects of the various eicosanoids to develop new therapeutic agents currently seems an unfultilled promise to medicinal chemists. Although these natural substances are highly potent effectors of various biological functions, their use as drugs has been hampered by several factors: (a) their

The ongoing development of potent. eflèctive. and long-

chemical complexity and relative instability, which have

lan by GlaxoSmithKline) for continuous intravenous infusion in patients suffering from primary pulmonary hypertension (PPFI). The solution for infusion is prepared within 48 hours of expected use because of its limited chemical stability. The potent vasodilatory, platelet antiaggregatory effect and vascular smooth muscle aiitiproliferative effect of this naturally occurring cicosanoid produce a dramatic hut shortlived (half-life less than 6 minutes) therapeutic effect in PPH patients. Continuous, uninterrupted admninistratioti of the drug by portable infusion pump is necessary. however. to prevent sytnptoms of rebound pulmonary hypertension. To ensure proper use of this therapy, its distribution is relatively

limited, to some extent, their large-scale production and for-

mulation for clinical testing; (b) their susceptibility to rapid degradation (Fig. 24-3). which limits their effective bioactive half-life; and (c) their ability to affect diverse tissues particularly the gastrointestinal tract, which may lead to

te

DEVELOPMENT OF PROSTACYCLIN-DERIVED PRODUCTS

Is

severe nausea and vomiting) if they enter the systemic circu-

d

lation. even in small amounts. Caution is always recommended with the use of prostaglandin analogues in females of childbearing age because of their potential for inducing dramatic contraction of uterine muscles, possibly leading to miscarriage.

Several approaches have been used to overcome these difficulties. First, structural analogues of particular eicosa-

acting forms of naturally occurring PGI2 is an excellent illustration of strategies that capitalize (in the beneficial but shortlived biological effects of eicosanoid derivatives. PGI2 itself is currently marketed as the sodium salt epoprostenol; Flo-

restricted.25

noids have been synthesized that are more resistant tochemical and metabolic degradation but maintain, to a large extent.

C00

desirable biological activity. Although commercial production and formulation may be facilitated by this approach. biological potency of these analogues is tisually reduced by several orders of magnitude. Also, systemic side effects may troublesome because of broader tissue distribution as a result of the increased biological half-life. Structural alterations of the eicosanoids have been aimed primarily at reducing or eliminating the very rapid melaholism of these potent substances to relatively inactive metabo-

v t,

•

lites (see Fig. 24-3). Several analogues are presented in Table 24-2 to illustrate approaches that have led to potentially use•

•

lul eicosanoid drugs. Methylation at the 15 or 16 position will eliminate or reduce oxidation of the essential 15-(S)alcohol moiety. Esterification of the carboxylic acid function may affect formulation or absorption characteristics of the cicosanoid. whereas esterase enzymes in the bloodstream or tissues would be expected to regenerate the active therapeu-

tic agent quickly. Somewhat surprisingly, considering the restrictive configurational requirements at the naturally asymmetric centers, a variety of hydrophobic substituents including phenyl rings) may replace the saturated alkyl chains, with retention of hioacsivity. A second major approach has beeti aimed at delivering the desired agent, either a natural eicosanoid or a modified analogue, to a localized site of action by a controlled delivery method. The exact method of delivery may vary according to the desired site of action (e.g.. uterus, stomach, lung) hut

has included aerosols and locally applied suppository, gel formulations, or cyclodextrin complexes. The recent commercial development of PGF-type derivatives for use in the eye to lower intraocular pressure (lOP) in glaucoma (discussed below under the heading. Prostagland ins for Ophthal-

mic Use) relies on their potent therapeutic effects coupled

Three more-stable derivatives of PGI2 are being developed to extend the duration of action of this (1mg to improve the safety and convenience of PPH therapy and, perhaps. broaden the therapeutic indications for its use. Treprostinil (Remodulin) with an extended half-life has been developed for continuous subcutaneous injection for PPM patients. This

C00

824

Wi!.nni and GIsvolds Textbook

of Orgwiic Medkis:aI and Pharmaceutical Chemistry

Prostaglandin Analogues under Investigation as Receptor Ligands and Future Drug

TABLE 24—2

Candidates

Butapros

EPrrixcptor Iitmnd

BW245C: R=H

ligancic

A= HO

BWA 868C: R = A

HN

HO

0 Cicaprost

IP-reccplor hgnnd

CH3

HO ligand nitiiiIcer

EnprosUl (Roche)

Enisopmst (Scarle)

Orphan statue cycltstpurinr oxiOI)

Gemirprosi Cenagern by Ono

Abonitacie:it

HO

HO ligami

COOH

N— H

—

Chapter 24 • Prusraglt,ndiiss. Leuko:rie,,es, uiul OiIwr Eieo.ca,ioidc

825

TABLE 24—2—Continued rP-rcccpior tigand

SQ-29S48

'II H

Suiprostone (Glotil Bases Dali Saj,ilana

Fannacculicat)

U.4Mit9

ligund

Osyitixic

TP.rcccplor ligund

method of administration and longer hall-life would markedly improve the convenience and safety of 'prostacyclin" therapy in PPH patients. Localized intermittent subcutaneous administration of Uniprost is proposed for the treatment

of critical limb itchemia. Another stable derivative of PGI2. iloprost. is intended for nasal inhalation to provide a direct vasodilatory effect on pulmonary blood vessels and thus decrease vascular resistance. Currently available in Europe. patients inhale 6 to 8 pulfs of aerosolized iloprost every 2 to 3 hours. Side effects such as coughing, headaches, and jaw pain have been re-

ct-i3

ported. COOH

EICOSANOID RECEPTORS

CH3

Another approach to developing new therapies based on the known biological activities of the prostaglandins and leukotrienes requires characterization of the naturally occurring tissue receptors for these agents. A thorough knowledge of

the tissue distribution (localization) of such receptors and their binding characteristics would allow the design of receptor-specific agonists or antagonists that might not possess

An even more chemically and biologically stable derivative of PGI2 is ber4prost, which is being evaluated in an oral formulation for the treatment of early-stage pulmonary peripheral vascular arterial This prostacyclin has been approved for use in Japan but not yet in the United States.

the same limitations as the natural eicosanoids but could affect tissue function nonetheless. An excellent historical description of prostanoid receptor and a isolation and characterization has been more recent review of developments in this field is available." Basically. prostanoid receptors are identified by their primary eicosanoid agonist (e.g.. DP. EP, IP. and TP). although subclassification of PGE receptors has been neces-

826

Wilson

and Gisiold.s Teul,ook of Organic Sfrd,e,nal ant! Phannaceuthal Chen,i.sirs and EP.1). in fact, the existence of

nary (e.g.. EP1

types is relatively low (30 to 50C/e). All prostanoid receptors. however, are believed belong to a 'rhodopsin-type" super.

subtypes of the

and receptor (EP1,5 TP receptor (TP.,. TP11 has been proposed. Complete charac-

of receptors that function via G-protein-.coupkd

teri/ation of receptors (and subtypes) includes tissUe localization. biological cffect produced, cellular signal transduction mechanism, inhibitor sensitivity, protein stflicture, and genetic origin. Not all receptors or subtypes have been com-

transduction mechanisms. Three general classes of proctan. oid receptors are proposed I: (a) relaxant, including DP.

El'.1, and ii', which promote smooth muscle relaxation hs raising intracellular cyclic adenosine monophnsphate (cAMP) levels: (b) contractile, including El'1, FP. and Th which promote smooth muscle contraction via calcium ion

pletely characterii.ed in this way, hut significant progress toward this goal has occurred recently. Table 24-3 indicates characteristics of the prostanoid receptors identified thus far. Although receptor studies have required the use of nonhuman species (principally the mouse hum also the rat, cow. sheep, and rahhiu. a high correlation of structural homology of receptor subtypes between species (—(10 to

muobilizatiomE and (e) inhibitory, such as El'5. which prevents

smooth muscle contraction by lowering intracellular cAM) levels. Although structural and functional characieriaitiix of prostanoid receptors has permitted the identification and differentiation of selective receptor ligands (Table 24.3. nih agonists and antagonists), overlapping tissue distributinri'

(has been

observed, while structural homology among receptor sub-

TABLE 24—3

Receptor

Prostanoid Receptor Characteristics Principle Ligands

up

TissuelAction Ikum/muu.ctc relaxation

BWA86$C

Brain (kptonieninges)/ sluep induction

POE,

Kidney/papitinry ducts

I 7-ptueumy)-I'GE,

i.umuglbronchoconstriu,miiun

Sulprosmuuiue

Stsumavh/snwoth

BW2'LSC EP>

Itoprusi

Transduction l'cAMP/Gs

Gene Knockout Effect Not available

Not available

u,uusctc cs,mraction

Bmnmutopoist

(indmicibkt

PGt; p(;E

I.nnglbronchodiiation

BUtapnx.t I ntisoprosmot

tlturnms/implnntauiu,n

POE.;

(iiislricliuntisccrcmomy

PP>5 J. cAMP/C,

Sutprostone

Guistncicytopromcctivc

EP0, I cAMP/G, EPs' I cAMP/G,

IcAMP/G,

.LOvuiaiion .LFtmiiIi,amion

INn' hypertension

isoprosuut t-nturoslut Gemeprosu

iii',

POE

Misoprostol

Lilerus/Inhihims contraction

t3rain/fevcr response

Pyrngcn rcvponse

Ipi tumos cr105

Duemus ancriosusirelaxunt

TcAMPIG,

Kidiuey/glomcruius

Patent ductus armeriina>

.I.Bone resorption

Gastric anlnmnt/unucoun secretion

Uterus/endornecrium Eye/decreases inmraocular pressure

PP

IPI turnoverlG5

Lost

IcAMP/Os

Imromnbosis

Corpus luteu,u/Iutcoiysis

Curboptmt

Lung/bronchoconstrtctinn

I.otaiioprost Untiprostouls'

i'rasoprosm Itinuatuprust tP

TI'

Pot. linprost

Arturriu.s/dilotion

Cucaprosm

t)RG ncuronslpain

luorapausm

Kidney/aficreni amienoles I IGFR)

TXA2

Lung/bronchuctunsmrwtton

.LIn)lamntatory edeno

cAMP

Kidney/I. (WR

Finn

SQ-2954$

Artcricskonstricmion

tJ-466(')

'llmymus4 immuture thymocytec

S.. NIvuuolo.

Y

not t shukuhi. F

Re

75

I 15.5—I

'lull

TI'11 IcAMP

tBtceding

Chapter 24 • Prostaglwzdins, Leukoirie,ie,s. and Other and common signal transduction mechanisms present formiobstacles to the development of specitic pharmacological therapies.

Eico.canoid.s

8.27

PGE1. aiprostadil (Prostin VR Prostaglandin E1, USP. Pediatric), is a naturally occurring prostaglandin that has found particular use in maintaining a patent (opened) ductus arteriosus in infants with congenital defects that restrict pulmonary or systemic blood flow. COOH

EICOSANOIDS APPROVED FOR HUMAN CUNICAL USE dinoprost (Prostin F2 Prostaglandin Alpha), is a naturally occurring prostaglandin that was ad-

ministered intra-amniotically to induce labor or abortion within the Iirst trimester.

HO HO

Alprostadil must he administered intravenously Continually at a rate of approximately 0.1 pg/kg per minute to temporarily maintain the patency of the ductus arteriosus until corrective surgery can be performed. Up to 80% of

This product. which was supplied as a solution of the tromethatnine salt (5 mg/mL) for direct administration, is no longer available in the United States for human use but is still formulated for veterinary use as described elsewhere in this chapter.

dinoprostonc (Prostin E2. Prostaglandin E3. (ervidill. is a naturally occurring prostaglandin that is administered in a single dose of 20 mg by vaginal suppository to induce labor or abortion.

COOH

circulating alprostadil may be nietaboli,.ed in a single pass through the lungs. Because apnea occurs in 10 to 12% of neonates with congenital heart defects, this product should he administered only when ventilatory assistance is immediately available. Other commonly observed side effects include decreased arterial blood pressure (which should be monitored during infusion), inhibited platelet aggregation (which tnight aggravate bleeding tendencies), and diarrhea. Prostin VR Pediatric is provided as a sterile solution in absolute alcohol (0.5 mg/mUJ that must be diluted in saline or dextrose solution before intravenous administration. A liposomal preparation is available (Liposome Company) to extend the biological half-life of the active prostaglandin. Aiprostadil (Caveiject) is also available in glass vials for reconstitution to provide I mL of solution containing either 10 or 20 pg/niL for intercavernosa) penile injection to diagnose or correct erectile dysfunction in certain cases of impothis therapeutence. A urethntl suppository is also tic use has been all hut eliminated, however, by the availability of orally administered Viagra.

Prostaglandin E7 Cyclodextrin. HO

HO

Carboprost tromethamine. Ca,boprost Tmmethamine. (Hcmabate). is a prostaglandin derivaive that has been modified to prevent metabolic oxidation of the IS-position alcohol (unction. HO

The cyclic polysac-

charide complex of PGE1 (Vasoprost is available as an orphan drug for the treatment of severe peripheral arterial occlusive disease when grafts or angioplasty are not indicated. Cyclodextrin complexation is used to enhance water solubility and reduce rapid metabolic inactivation.

Misoprostol.

Misoprostol. I 6-tR.S)-meihyl- 16-hydroxyPGE1 methyl ester (Cytotec), is a modified prostaglandin analogue that shows potent gastric antisecretory and gitstroprotective effects when administered orally. COOCH3

.CH3

HO

CH3

This derivative is administered in a dose of 250 pg by

HO

Jeep intramuscular injection to induce abortion or to ameliorate severe postpartum hemorrhage.

Misoprostol is administered orally in tablet form in a dose

828

WiLwn and Gisvold's Textbook of Organic Medicinal and Plaarmareuihal ('Iwmistrv

of 100 to 200

4 times a day to prevent gastric ulceration

in susceptible individuals who are taking NSAIDs. Misoprostol is combined with the NSAID diclofenac in an analgesic product (Arthrotec by Pharmacia) that is potentially safe for long-term antiarthritic therapy. This prostaglandin ative should be avoided by pregnant women because of its

Travoprost. Travoprost (Travatan) is supplied as a 2.5. mL sterile 0.(XWA- ophthalmic solution in a 3.5-mi. con. tamer. Travoprost is claimed to bc the most potent and FP. Cautions and specific analogue in this product side effects are similar to those given above. CH3

potential to induce abortion. In fact, the combined use of intramuscular methotrexate and intravaginal misoprostol has been claimed to be a safe and effective. noninvasive method for the termination of early pregnancy.3°

PROSTAGLANDINS FOR OPHThALMIC USE Several proslaglandin analogues have recently come to mar-

ket for the treatment of open-angle glaucoma or ocular hypertension in patients who have not benefited from other available therapies. These products are marketed as sterile solutions for use in the eye (as indicated below). Each of these agents is presumed to lower lOP by stimulation of FP receptors to open the uveoscleral pathway, thus increasing aqueous humor outflow. Commonly occurring side effects reported for this product group include conjunctival hyperemia, increased pigmentation and growth of eyelashes, ocu-

CF3

Unoprostone.

Unoprostonc (Rescula) is supplied as a 0. 15% sterile ophthalmic solution. Unoprostone is somewhat

unusual, in that it is a docosanoid (22-carbon atom) PG, analogue marketed as the isopropyl ester. The naturdl position alcohol is oxidized to the ketone, as would pected to occur in vivo. Cautions and side effects am similar to those given above.

lar pruritus, and increased pigmentation of the iris and eyelid. Contact lenses should be removed during and after (15 minutes) administration of these products.

Bimatoprost.

Bimatoprost (Lumigan) is supplied as a sterile 0.03% ophthalmic solution in 2.5- and 5.0-mL sizes. The recommended dosage of bimatoprost is limited to one

drop into the affected eye once daily in the evening. Increased use may decrease its beneficial effect. If used con-

H

currently with other lOP-lowering drugs, a waiting period of 5 minutes should separate administrations. HO

H

VETERINARY USES OF PROSTANOIDS

Latanoprost.

Latanoprost (Xalatan) is available as a 0.005% sterile ophthalmic solution in a 2.5-mL dispenser bottle. Latanoprost is also marketed as a combination ophthalmic product with the f3-adrenergic blocking agent timolol. which apparently enhances lOP-lowering by decreasing the production of aqueous humor. Cautions and side effects are similar to those for other ophthalmic prostanoids.

H0.

CH3

_(

CH3

Since McCracken and coworkers demonstrated that acts as a hormone in sheep to induce disintegration of liar corpus luteum (lutcolysis).32 salts of this prostaglandin and a variety of analogues have been marketed to induce or chronize estrus in breed animals. This procedure allows ficial insemination of many animals during one insemination period. The following two products are currently availuhk for this purpose.

C7oprostenol Sodium.

Cloproslenol sodium lEsion mate) is available as the stxlium salt from Bayer Agilculluol Division or Bayvet Division of Miles Laboratory as an aquc.

ous solution containing 250 mg/mI. HO

Chapter 24 •

l,e,,An:rie,u'.v. and O:lwr Ejcrixani,jdx

829

Dinoprost Tnmethamine. Dinoprost tn luethalnine Lutalyse) marketed by Upjohn (veterinary) is a pH-balanced aqueous soiLulon of the trimethylammonium suit of (5(1 mg/nIL).

23. Warner, T I)., C,iuliano. F.. I.. oat.: Proc. Nail. Acad. Sci. C. S. A. 96:756375(,,8. 1999. 2.1. Susanna. R.. Gianipaiii, J.. Barge'.. A. S.. et al.: Ophthalmology IllS'

EICOSANOIDS IN CUNICAL DEVELOPMENT FOR HUMAN TREATMENT

29. Coleman. R. A., SunlIt. W. I... and Narutttiya, S.: Phannacol. Rev. 46: 205—229, l994

259—263, 2(8)1.

25. Am J. Health.Syst Phanti. 53:976 and 91(2. 1996. 26. Vu/a. C. 0., Snottier, S., Morelli. S.. eta).: Heart 86:661—665, 2001. 27. Nagaya. N., Sliimi,.u. Y.. Satolt, T.. ci at,: Heart 87:3441—345. 2)102. 28. l,tevre. M., Maraud, S.. Besse. II.. ci al.: Circulatiim (12:426—431, 2(88).

Numerous prostagiandin analogues are under investigation treatment of human diseases (see Table 24-2). Efforts are being focused on the areas of gastroprotectuon for antiulcer therapy. fertility control, the development of thrombolylics (e.g.. prostacyclin or thronthoxane synthelase inhibitors) to treat cerebrovascular or coronary artery diseases, and the development of antiasthmatics through modulation of the lipoxygenase pathway. Future application of cicosanoids to the treatment of cancer, hypertension, or immune system

thsorders cannot be ruled out, however. Thus, although progress has been slow, the expanded use of eico.sanoids or

deosanoid analogues as therapeutic agents in the future is almost ensured.

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Kur,.rok. K.. and Liett. C Proc Site. Esp. Blot. 28:268. 1931.

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'. Beegcimni, S.. et at.: /iOn Otcm. Scand. 6:5th. t962. 4. Nicolaou. K. C.. and Pcta'.is. N. A.: In Wdtis. A. L. led.). Handbook of Eicus,uioids: Piostaglandins and Related Lipids. vol. I. part I). t(oca Ruin, Ft.. CRC Press. 1987. pp. I-IS. 5. Flower. K. 3., Blackwelt. G. 3.. and Smith. 0, L.: In WilIri. A. L. led.). Handbook of F.icosani,ids: Proslagtandins and Related Lipid.s. sot. It. lInen Raton. FL. CRC Press, t989, pp. 35—46. 6. Pantham, N.J., Day. R. 0.. and Vnn den Berg. W. B.: Agent'. Actiim'. 41:C145 .('(49 1994. 7. Tsai, A.-L.. and Kulinace. R. J.: Prostaglandins Other L.ipid Mediators 62:231-254, 2t1(X).

5. Smith, W. I.., and Dewitt, 0. I..: Ads. Immunol. fi2:l67—2l5. 996. 'I. Vane. J. R.. Bakhle, Y and Boiling, R. N,: Annu. Rev. Ptiarniaciit. 38:97—t2C). (998. UI.

Lands. W. Ii. M.: Prostaglvindios t.cukin, Essent. Fatty Acids 63: t25—126, 2t148).

II. Narumiya. S.. Sugimoto. Y.. and tishikubi, F.: Pttysitit. Rn'.. 79: 1193—1226,

999.

(2. Kuhn, H.: t'rostaglnndin'. Other t.ipd Mediators (i2:255—27(t, 2(1(10. f(, Bell, R. t.. Summers. J. B.. anti Ham'.. R. R.. Anon. Rep. Med. ('hem 32:91—100. 1997.

(3. Seciektik. A.: Adv. Prostaglandin Titromboxane Leukot. Re'.. 22: 185— 98. 1994.

IS. Mvtrnett. I.. J.. and Fling. T. F..: Rev. Riochem. Toxicol.5:l35. 1984. 6. Robertson, I. (I. C.. ci at.: Cancer Res. 43:476. t91(3. Ii. Lands. W. F. M.. Jr.: Trends Pliurniacol. Sri 1:7%. 1981.

IS. Romc. L. H.. and I.ands. W. Ii. M.: Proc. Nail. Aced. Sci. U. S. A. 72:41(63, 1975.

IS. Higgs. G. A. 0 ul.: Proc. NatI. Acad. Sci. U. S. A. 1(4:1417. 191(7. SI. Haitel. A. M.. and Lands. W. F. M.: Biocliem. l'ttarmacol 31:33(17, (982.

Kuehi, F. A.. ci ul.: In Ramwell. P. led.l. Prostaglundin Syntheta.se tnbibitors: New Clinical Application'.. New York. Alan R. Liss, 1980. pp. 73.8(1.

Cryer. II., and Feldman. N.: Am. J. Med. 1114:413-421. (998

3)). llausknecht. K V.: N. EngI. 3. Mcd 333:537-541). 1995 31. Stiaril, N. A.. l)avis. T. t... and Williams, G. W.: J. Phartn. Pltarmacol SI :685.-6')4, 1999. 32. McCracken, S. A.. ci at.: Nature 238:129, (972.

SELECTED READING Bailey. I. M. led.): Priistaglauidtns, l.ctiki,incnes. unit New Yi,rk. Plenum Press, 1985. Bali. 0. 4).: 5.Lipoxygenasu. itthibitors and their anti-intlammatory aclisttics. Prog. Med. Client. 29:1—63. 1992.

Chandnt. R. K. (cdl: Health Effects of Fish and Fish Oils. St. John's. ARTS Iliiunedjeat Pulilishen, and Distributors. 1989. Ciilteti, N. N. let).): Bioliigicul Pniicctitin with Pru'.iaglauidins iii'. I and 2. flora Raton, FL, CRC Press. l91t5. (986. Dunn, M. J., Patrono. C.. and ('moth, 4). A. led'..): Renal eicosauioid.s. Ads. Lap. Med. flint. 259:1—421. 1989.

lidilvi'.). I.. Ii.. and Kindahl. H. leds.t: Prosiaglnndins in Animal Reproduction. New York, Elsevier, l9%4. Fukushitna, M.: Biological activities atid mechanisms of action of PGJ. and related conupintnds: ;m tipilate. Priistaglandins Leutktn l,ssent. Fatty Acids 47:1-12. 191)2. Gryglewski, R.J..anvt Stock. 4). led'..): Priusiacyelin and Its Stable Analogue lloptnst. New York. Springer-Verlag. l987

(iryglcwnki. K. J..

A., and McGill, J. C ledsJ: Proslacyelin

Clinical TunIs. New York. Ruseit Press. 1985. Hillier. K. (Cd.). Advances in Licosanoid Research. stils. I —4. Bosiott, NIP Press, 191(7—1988.

t,autds. W. F.. N.. and Smith. W. L. (edv.(: Prosiagtandmns and aracliidonate inetabolitis. Enzyiitnl. 86:1—7)15. 1982.

Icier. A. M.. and ()ee. M. H. (eds.l: Lenkotrienes in cardiovascular and pulmonaiy function. Prog. fin. t3iol. Res. 199:1—270. 19145. Pace-Asciak. C. R.: Mass spectra n) ltrostaglaltdins and related products. In Satttuelssoti. B.. and Patiletli, R. led.): Ads. Prostaglundin Thtroml.ettkot. Res. 18:1 —565. (989

Rainsfoni. K. 0.: Anti.Inllaminatoiy and Anti.Rheumattc Drugs, nil'.. Boca Raton. FL. CRC Press. (985.

I —3.

Robinson. H S.. and Vane. .1. R. (cds.l: Prosinglnndin Syniheia.se Inhibitors. New York. Raven Press. 1974. Rc,kach, J. led.): attd l.iposygena.ses. Ainstenlatit. Elsevier. 1989.

Rit,.icka. 'I'.: Ficosanoids and the Skin. lhiwa Raton, FL. CRC Press, 199(1. Schror, K.. and Sinainger. H. led'..): Prosiaglatidins in Clinical Research:

Cardiovascular System, vol.3(11. New York, Alati K. I.iss, 1989. Simopottlns, A. P., Kifer. R. R., and Martin, R. F..: He.tltlt El'fectsoiPolyunsuiurnted Fatty Acids in Seafood,,. New York. Acztdetttic Press. 1986. Stansbv. bE F.. led.): Fish Oils in Nutrition. New York. Van Nostrand Reinhold, 199(1.

Thaler-Dun. II., dePaulet. A. C., and Paoletti, K.: Icosanoids and Cancer. New York, Raven Press. (984. Vane, J. R.. and O'Grady. 3. (etis.l: Therapeutic Application'. of Proataglan.

din'. Boston. Edward Arnold, 993 Watkins. W. 0.. Peterson, M. B.. and Fletcher. 3. R. teds.): Prostaglandin.'. in Clinical Practice. New York, Raven Press, 1989. Willis, A. L. lcd.): Handbook of Eirissatnoids: Prustaglaildins vital Related Lipid.'., '.'ol. II. Born Raton, FL. CRC Press, 1989. Zor, U.. Naor, Z.. and Danon. A. ted.'..): lii Brjquet. P. led.). Leukotruenes and Prostanoids in Health and Disease, New' I'rvnds in lipid Mediutor,. Research. vol. 3. Bawl. S. Karger. 1989.

C

H

A

P

T

E

R

25

Proteins, Enzymes, and Peptide

Hormones STEPHEN J. CURER AND HORACE G. CUTLER

Proteins are essential to all living matter and perlbnn nuinerous functions as cellular components. Fundamental cellular events are catalyzed by proteins called enzymes, while other proteins serve as architectural constituents of protoplasm and cell membranes. Most important are the classes of hormones that are characterized as proteins or protein-like compounds because of their polypeptidic structure. Protein chemistry, essential in understanding the inecha-

nisms of molecular biology and how cellular components participate in physiology, is also key to certain aspects of medicinal chemistry. An examination of the chemical nature of proteins explains the action of those medicinal agents that are proteins or protein-like compounds and elucidates their physicochemical and biochemical properties. This, in turn. relates to their mechanisms of action. Furthermore, in medic-

inal chemistry, drug—receptor interactions are directly related to structure—activity relationships (SARs) and aid in the process of rational drug design. Drug receptors arc considered to he macromolecules, some of which appear to be proteins or protein-like. Recombinant DNA (rDNA) technology' has had a dramatic impact on our ability to produce complex proteins and polypeptides structurally identical with those found in vivo. Many of the endogenous proteins or polypeptides have exhibited neurotransmifler and hormonal properties that regulate a variety of important physiological processes. rDNAderived technology products currently being used are discussed below in this chapter. Although this chapter reviews the medicinal chemistry of proteins, it includes some enzymology, not only because many drugs affect enzyme systems and vice versa but also because basic discoveries in enzymology have been practically applied to the study of drug—receptor interactions. Hence, a basic introduction to enzymes is included.

protein are made available in the form of protein sates, and these can be administered to induce a favorable balance.

Protein deficiencies in human nutrition are treated with protein hydrolysates. The lack of adequate pro

tein may result from several conditions, but the prohkm not always easy to diagnose. The deficiency may he due to insufficient dietary intake. temporarily increased (as in pregnancy), impaired digestion or absorption. liver malfunction, increased catabolism, or loss of proteins aid amino acids (e.g., in fevers, leukemia, hemorrhage. surgery.

burns, fractures, or shock).

Protein Hydrolysate.

Protein liydrolysate is a solution of amino acids and short-chain oligopeptides that represeni the approximate nutritive equivalent of the casein. lactalbu mm. plasma. fibrin, or other suitable protein from which It

is derived by acid. enzymatic. or other hydrolytic It may be modified by partial removal, and restoration ii addition of one or more amino acids. It may contain dextmse

or another carbohydrate suitable for intravenous infusion Not less than 50% of the total nitrogen present is in the form of a-amino nitrogen. It is a yellowish to rcd-amnkt

transparent liquid with a pH of 4 to 7. Parenteral preparations arc used to maintain a positive nitrogen balance in patients who exhibit interference with ingestion, digestion, or absorption of food. For such patients. the material to be injected must be nonantigenic and mnn4 not contain pyrogcns or peptides of high molecular weight.

Injection may result in untoward effects such

nausea

vomiting, fever. vasodilatation. abdominal pain, twitching and convulsions. edema at the site of injection. phlehith. and thrombosis. Sometimes, these reactions are due toinudc.

quate cleanliness or too-rapid administration.

PROTEIN HYDROLYSATES In therapeutics, agents affecting volume and composition of body Iluids include various classes of parenteral products. Ideally, it would he desirable to have available parenteral fluids that provide adequate calories and important proteins and lipids to mimic, as closely as possible, an appropriate diet. Unhlirtunately. this is not the case. Usually, sufficient carbohydrate is administered intravenously to prevent ketosis, and in some cases, it is necessary to give further sources of carbohydrate by vein to reduce protein waste. Sources of

830

AMINO ACID SOLUTIONS Amino acid solutions contain a mixture of essential arid now essential crystalline amino acids, with or without

(e.g.. Aminosyn, ProCalarnine. Travasol. Novamine). Al. though oral studies have shown a comparison between pro. tein hydrolysates and free amino acid diets.2 protein sates are being replaced by crystalline amino acid solutions for parenteral administration because the free amino acids

Chapter 25 • Profrmus.

and Pep:ide Hnnnoni'.s

831

are used more etliciently than the peptides produced by the cnLymatic cleavage of protein hydrolysates.5

PROTEINS AND PROTEIN-LIKE COMPOUNDS The chemistry of proteins is complex, with many facets not completely understood. Protein structure is usually studied in basic organic chemistry and, to a greater extent, in biochemistry, but for the purposes of this chapter some of the nwre important topics are sumtnarized, with emphasis on relationships to medicinal chemistry. Much progress has been itiade in understanding the more sophisticated features of protein structure4 and its correlation with physicochemical md biological properties. With the total synthesis of ribonuclease in 1969. new approaches to the study of SARs among proteins have involved the synthesis of modified pro.

I 0
,

a

C Ui

bond alignment effects are reproduced adequately in force field calculations using a three-term truncated Fourier series

(Eq. 28-20). Essentially, this torsion function introduces quantum mechanical efTects into a classical hall-and-spring system, which traiisliirms our model into a much more powerful tool, with a fraction of the computer costs in terms of CPU cycles compared with using quantum chemical calculations. V

-- coso) +

V.

— cos2ø) +

V

+ cas3O) (Eq. 28-20)

0

20

40

60

60

100

120

140

180

ItO

DIhedral Anglo

Figure 28—13 • A plot of Equation 28-20 with Vi = and V2 is a positive number. Note that this curve has

0.

symmetry. The second term in Equation 28-20 is used to repro-

duce ethylene-like torsion profiles about double bonds

Chapter 28 • Conipuuuional Clu'n,is:rv and Cennpurer-Assistecl 1)rug Design

929

prove the accuracy of the force field description. Many of these additional terms fall into the category of cross-terms, in which two motions or interactions are connected or correlated. For example, in small molecule force fields one might find stretch—torsion, stretch—bend, bend—bend, torsion—bend, and other interactions. Equation 28-21 shows a stretch—bend function. Some of these cross-terms have been

a,

a

shown to be more important than others. The purpose of

C UI

cross-terms is to give better geometric results, and they are particularly important in calculating the vibrational spectra.

=

0

20

40

60

80

100

120

140

180

180

Dihedral Angie

Figure 28—14 • A plot of Equation 28-20 with V2 = V3 = 0, and V1 is a positive number. Note that this curve has onefold symmetry. The interpretation is less straightforward than the second and third terms in Equation 28-20. The first term in Equation 28-20 is used to help reproduce torsion curves of the X following type. an

is

used to describe the torsional energy profile

(arising about = C,,,,2 double bonds), which has twofold symmetry. The true underlying chemical explanation for the sharp energy rise observed in rotating about carbon—carbon double bonds may be attributed to the breaking of the weak bond. The ir bond is a consequence of the overlap of two adjacent coplanar p-orbitals. Any rotation about the bond shifts the orientation of the p-orbitals. with = a reduction in the overlap and a concomitant rise in energy.

For example, ethylene, the simplest alkene. prefers a flat conformation with the dihedral angles at dihedral angle is either 0° or 180°. When the 90C the p-orbitals are orthogonal, and there is no overlap. Therefore, the energy is a maximum along the one-dimensional potential energy curve when is 90°.

(tr — ro) + (r' — r,,')l tO — ((i)

(Eq. 28-21)

Force field methods are fast and accurate if the potential energy functions and parameters within the potential energy functions have been carefully developed. in addition to cal-

culating molecular geometry. force field calculations are used to determine the energy between conformations.

GEOMETRY OPTIMIZATION It is important to be able to take a molecular structure in silico and subject it to energy minimization. This is the first step for force field and quantum mechanics calculations and for moleculardynamics simulations. Once a molecular structure finds a stable conformation, the physical and chemical properties can then be calculated. The goal of energy minimization (or geometry optimization) is to take a high-energy state, which is a function of the atomic coordinates, and to

reduce the energy by optimizing the geometry. In other words, minimizing the potential energy functions with respect to the coordinates reduces the steric and electrostatic

interactions. This is a type of calculus problem familiar to students who have ever had to locate the stationary points of a given equation. Recall that the extrema (maxima and minima) of a mathematical function fix). with one independent variable x. have first derivatives equal to zero.f'(x) = 0. The second derivativef"(x) will be positive if it is a minimum and negative if it is a maximum. Figure 28-15 shows

The physical significance of the V1 term is less intuitive. Setting the V2 and V,, terms to zero and assigning the term a positive value yields the curve shown in Figure 2814. The V1 term is used primarily as an additional way to increase the repulsive interactions between atoms that have

a 1.4 relationship that are not fully accounted for by the nonbonded terms. This situation is commonly found for elec-

tron-withdrawing groups X and Y. with torsion combinalions

'5

and

Radom, Hehre, and Pople were the first to give physical interpretations 01' these torsional terms!'2 For maximum flex-

ibility in developing force fields, it should be noted that the Vi, V2. and V3 terms may be either positive or negative. Although the discussion above focuses on carbon—carbon or carbon—hydrogen torsion angles. Equation 28-2() also ap-

plies to any other combination i-j-k-l. with any other elements from the periodic table used for i, j, k, and I. Given the number of drugs that have heterocycles, a Force field useful for drug design has to address many torsion angle combinations. Additional energy interaction terms may be added to im-

x

Figure 28—15 • An arbitraryr athematicalfunction with maxima and minima. The first derivative of a function is zero at a maximum or minimum, f'(x) = 0. The second derivative is positive (f(x) = + value) if the stationary point is a minimum, or is negative (f°(x) = —value) if the stationary point is a maximum.

930

Wits,,,, and Gis,'old'x Textbook of Organic Medicinal and Pharmaceutical Clienio:rv

an example of a function, fix), with two minima and two maxima.

Typically, a molecular structure is entered into a molecular modeling software package by template fragments or through a sketching mode. It is also possible to download

structures from structural databases. Structures built or downloaded do not have an optimum geometry based on the force field potential energy equations: i.e., they are not occupying the lowest energy state in vacuo. Minimization algorithms are written to take a starting structure and minimize the energy, which translates into the structure dropping into the nearest potential energy well on the conformational hyperenergy surface. The more complex the structure, usually the more minima are available in conformationa! space. Butane, a simple hydrocarbon, is an informative example. It has three minima available. Energy minimization requires a series of iterations because of the nonlinear nature of the force field potential energy functions. The general stratagem is to transform the full nonlinear optimization into a series of local iterative linearizations, and this approach works well. Atoms within a molecular structure are moved in small steps

in the direction that results in a decrease in the energy of the system. The size and direction of the steps are determined

by the specific method being used, based on Equation 283, and illustrated for a one.dimensional case in Figure 2816.

Geometry optimization may be divided into two broad categories: first-order methods and second-order methods. The former uses first derivatives to determine the step size

and direction, while the latter uses both first and second derivative.s. First-order methods include steepest descent

added to the coordinates at each step and is updated by a quick recalculation of the force field total energy. SD is the simplest approach."'° The step size in SD & is simply taken as a scaled negative gradient as shown in Equation 28-22. where V (del). a vector operator, is the gradient as defined by Equation 28-23 and A is a scaling constant.

The SD algorithm is inefficient when the potential energy curve is not very steep. So as the minimum is approached. where the slope of the curve is flatter. SD algorithms become

inefficient cotnpared with other methods. = —A(V,,E,,,,,)

V=

28.22)

(Eq. 28-23i

+

The CG method, outlined in Equation 28-24, is widel) It gives better convergence than SD algorithms. As the name implies, the previous step size along with current gradient as deterniincd by the total force field energy is used to determine the next step size. An additional sealing factor is found to improve results.

= r,, + e&,

(Eq. 28-24

The Ncwton-Raphson method uses information obtained by taking the first and second derivatives of the energy wiih respect to the coordinates.22 The combination of both first and second derivatives provides a powerful itiethod to locate minima. This may be a time-consuming process because of the matrix manipulations that must he undertaken for a 3N system, where N is the number of atoms. In Equalion 28-25. V2 is the dot product of V multiplied by itself. Note that V2 is a scalar operator.

(SD) and conjugate gradient (CG). The second-order method discussed below is known as the Newton-Raphson (NR) geometry optimization approach: there are many variations of this method. Again, the concepts of minimizing a function are not new; they were developed years ago. (The

+

d.

h= =V •V

=

+

(Eq. 28-25)

+

k) yt +

+

"Newton" in Newton-Raphson is Sir Isaac Newton.) The

= I—,

immediate goal of an energy minimization is finding a suitable displacement 4,, which, as stated above, is opposite to the potential energy gradient. In other words, the atoms are

None of the geometry optimization methods discussed finds the global minimum.

+

dr

+

(Eq. 28.2h)

moved in the direction of the forces. The displacement is

CONFORMATIONAL SEARCHING As indicated above, it is important to be able to eonformational space to determine what arrangements of atoms (conformations) are energetically feasible. Observed physical properties (e.g.. heats of formation) are statistical averages of all the conformations available. Most organic molecules have multiple energy minima. In the case of drug design, it may be important to sample the possible number

a

of conformations a drug molecule can adopt. Usually, a drug in the drug—receptor complex adopts a bioactime

C

ho,, that differs from any of the local minima or the global minimum. From the analysis of many lead and drug pairs. the average drug-like molecule has more degrees of freedom

(i.e.. is more flexible) than lead-like compounds. Initially. this may seem counterintuitive. since the mission of a drug DIstance

FIgure 28—16 • The direction of the step size in an energy minimization is toward the minimum value.

is to have its functional groups bind to complementary functional groups of the receptor. It turns out that a flexible drug is superior to one with a locked conlorntation because thc exact orientation in a eonformationally constrained molecule

Chapter 28 • Compiouzionul C6e,ni.crrv and

may not be optimal for interactions with the receptor. Moreover. the potential supenonty of a flexible drug can be understood when one considers that both receptor and small mole-

cute must mold themselves to form the drug—receptor complex. A flexible drug can contort itself more easily to reach the binding pocket and then adjust itself accordingly to form the necessary interactions. A rigid drug with its functional groups locked into place may he more limited in its ability to get to the target site and, once there, to position itself correctly. Of course, based on the Koshland induced fit hypothesis, it is known that both small molecules and macromolecules adjust themselves to form protein—ligand complexes.

Before conformational searching is discussed in any detail, it is critical to have a common vocabulary. The terms conformer and conformation can he dertned in reference to the butane potential energy curve (Fig. 28- I I). There are an

infinite number of conformations on the curve, since the distance between any tsvo points on any curve may be as small as desired, confonnat ions refer to both maxima and minima and all positions in between. A conformer, on the other hand, refers to the conformation at the bottom of the potential energy well, which is a minimum. Looking at the simple case of butane, it is easily seen that there are three

potential energy wells. Every molecular structure has a

to do the calculations is to look at all possible axial and equatorial confonnations. With cyclohexanol. this is not difficult and can be done by manually altering the orientation of the OH group. For more complex structures. conformational searching routines must be used.

molecular structure would be energy minimized to the ç'uuehe conformer. If we started on the other side of the 1200

barrier, where the dihedral angle was 150°. the molecular structure would bc energy minimized to the a,,:, conformer. Second. some conformations arc more important than others. Third. as noted above, many physical problems are a consequence of a statistical average of the conformers present. Fourth, having a conformational search algorithm is a check against having biased structural data. In the case of butane, if only anti butane were known, there would be a lot of information missing. The majority of druglike molecules are structurally more complex than butane, but this hydrocarbon is a str.iightforward example. The importance of knowing available conformations flr property predictions can be illustrated by looking at substituted cyclohexane. For cyclohexanol. the axial:equatorial ratio is derived by using Boltzmann statistics to calculate the ratio. Equation 28-27 shows the Bollzmann equation. where is

Jr

=

(Eq. 28-27)

Table 28-I shows the three possible axial and equatorial conformations. Substitution in Equation 28-27 generates the calculated ratio of each conformer. Because MMFF94 was parameterized to reproduce the quantum tnechanical calcula-

tions, it is illustrative to look at the ratio calculated with MMFF94. The Boltzmann-averaged distribution may then be compared with the experimental data as well as the other force field results. Equation 28-28 outlines the procedures for calculating the

denominator in Equation 28-27. Note that in Table 28-I. entries I and 2 (as well as 4 and 5) are equivalent in energy. with relative conformational energies of 0.000 kcal/mol and —0.323 kcallmol. respectively. Consequently. the frequency

factor is 2 for both cases. The sutnniation of Equation 2828 is shown in Equation 28-29 to be 4.057. —fl 1W

=

-I-

(J 11111

—

+

tential energy lunctions are being minimized, not the geometry. Geometry optimmuzalion is the equivalent term, for the structure is being optimized according to the force field equa-

Why is it necessary to explore conformational space? First, as discussed above, energy minimization algorithms are designed to seek the nearest minimum to the starting position. So lbr butane, if we had an initial input geometry dihedral angle was 900. the in which the

(Eq. 2(4.2(0

+

= 2(X) + 0.715 + 1.164) + 0.1(42 = 4.057

(Eq. 28-29

The ratio lhr each entry in Table 28-I can be calculated by using Equation 28-27. It is more interesting to look at the summation of the total calculated equatorial versus total axial cyclohexanol conformations, which, on a percentage basis. is calculated by Equations 28-30 and 28-3 I. MMFF94

results give approximately 67% equatorial and 33% axial. This is in close agreement with the Hariree-Fock (HF) 631 G(d) quantum mechanical calculations of 66% equatorial and 34% axial, which is in reasonable agreement with experimental data. The calculated percentages with MM3 are 82% equatorial and 18% axial, while the calculated percentages

with the Tripos force field yield 46% equatorial and 54% axial. In general, the Tripos force field is qualitative (at best) and does not give particularly good energy values, so one must be cautious when trying to make accurate predictions using force field methods. —

x lOO'4 =

=

[2.00+0.7(5]

1./RI

(100%)

(l(x)cf) = 66.9%

(Eq.

is the probability of finding one conformation. f

a frequency factor indicating the degeneracy of the energy.

E1 is the relative energy (kcal/mol). R is the gas constant (0.0199 kcal/mol-K), and T is the temperature (K). For room temperature calculations, the product RT is 0.59 kcal/mol. If one look a single conformation of axial cyclohexanol and compared it with a single conformation of equatorial eyclo-

931

hexanol. an erroneous answer would result. The right way

global minimum, the absolute lowest energy, but there are many minima. For butane, the global minimum corresponds to the anti conformer. One speaks of energy minimization. not energy optimization (discussed above), because the po-

tions.

sied !)ruj,' Desig,.

x tt)OM' =

1

( lO()%i

J 1160 + 0 IX' =

= 33.lci

(Eq.

932

Wilxo,,

and Gisrolds Textho(,k of Organic Medicinal and Pl,amzaceuiicai C7,ennclrv

Three Axial and Three Equatorial Conformations of Cyclohexanol With Their Relative Energies Calculated Using Force Field (MMFF94. MM3. Thpos) and Ab Initlo Quantum Mechanics TABLE 28—1

(6—31G(d,p) or 6_31G**) Conformer

MM3

Sybyl

MMFF

0.000

0.129

OA)0O

0.000

0.0(5)

0.129

0(8)0

0.000

3

0.942

0.063

0.199

0.2(8)

4

0.834

0.000

0.323

0.244

0.834

0.000

1)323

((.244

2.637

0.05)

1.011

1.632

81.5:18.5

46.2:53.8

67.0.33(1

66.2:33.8

0.88

—0.09

0.42

0.4))

No.

H

I

2

Ii'

6

Ratio

HF

The goal ofconformational searching is to lund all possible values of the dihedral anglc.s that could be assigned to each

According to Equation 2-30. the nutnbcr of conformations generated rises exponentially with the number of bonds to.

rotatable bond in a molecular structure. Conformational

tated. Torsion angle driving is GS. while the rest of the

searching may be divided into two general categories: ,cysh'malu' and nans stemauc searching. As the name implies. systematic searching uses methods that are guaranteed to lund all minima within the defined search parameters, while nonsystematic searching uses statistical approaches. Systematic searching includes grid searching, torsion driving, and constrained searching. Nonsystematic searching includes dynamics, stochastic (random), and distance geometry. Systematic searching has been described as an exhaustive but the success is a sampling of confonnational function of the number of increments used to explore each

structure (with the exception of the torsion being systeniatically rotated) is energy minimized. Many programs have this feature, and accurate conformational energies are obtained

rotatable dihedral angle. No conformation will be over-

the cartesian coordinates arc randomized with a "kick." Ii the randomization is not large enough, the structure will return to its starting points. Too large a perturbation generates unrealistic high-energy conformations. The geometry is energy minimized with a force field, and the newly generated structure is compared with the original

looked (unless the search parameters are not small enough).

A simple analogy should make this clear, Imagine walking along a paved highway blindfolded (not recommended) with the goal of discovering all possible potholes. The number of potholes that may be located is a function of the step size and the distance traveled. The longer the gait, the faster one

travels down the road, but with a reduced probability of finding all the potholes. Systematic searching generally can-

not handle solvents, and the method is only amenable to searching fewer than 1(3 dihedral angles, because of the ex-

ponential explosion of possible conformations that results (see Equation 2-30 in Chapter 2). Large amounts of computer time are expended because small dihedral angle increments are required for each rotatable bond. In grid searching (GS). each torsion angle is examined, but the structure is not subjected to geometry optimization.

with the minimization. Nonsystematic searching typically is more suitable for larger molecules, and solvenis may be included.707' In general, more lime is necessary to apply statistical analyses for the "completeness" of a search. Although stochastic searches are useful, there is an inherent incompleteness to them. Stochastic searching can use either internal or canesian coordinates. From a staning low.cnergy conforntation.

structure according to the Metropolis algorithm (MA).72 The current conformation is compared with the newly generated one. If the energy of the newly generated conformation is lower than the energy of the original conformation, the new one is accepted. If the new conformation has a higher energy. there is a statistical chance it may also he retained. In this second case, a Boltzmann factor is calculated (Equation 2827). which is then compared with a random number between

0 and I. If the Boltzmann factor is less than the randomly generated number, the conformation is accepted; otherwise. it is rejected.

Chapter 28 • Computational C'hemixtry and C'oniputer-Asxi.crcd !)rug I)estgn With all methods, there are strengths and limitations. Conformational searching is no exception. A comparison of the methods was carried out on cycloheptadecane in an effort to find out 'what confonnations are significantly populated at room temperature or within, say 3 kcal/mol of the global minimum?"73 The authors reached the following conclusions: (a) the effectiveness of the search appears to depend highly on the method used, and (b) except for distance geometry, all methods could locate the global minimum: none of the methods found all 262 low-energy conformations in a single search. Because of the importance ofconformational searching, newer algorithms have been developed since this benchmark study.

The Confort algorithm, developed in the laboratory of

933

MOLECULAR DYNAMICS SIMULATIONS The molecular configuration is a function of time. Molecular systems are not stationary; molecules vibrate, rotate, and tumble. Force field calculations and the properties predicted by them are based on a stationary model. What is needed is some way to predict what motions the atoms within a molecule will undergo at various temperatures. Molecular dynamics (MD) simulations use classical mechanics—force field methods—to study the atomic and molecular motions to predict macroscopic properties.75

MD simulations have the potential to reveal important insights into drug—receptor interactions, but some important assumptions should be reviewed:

Robert Pearlman, performs a systematic search over all possible combinations of "worthy dihedral angle ranges" rather

I. Molecular systems obey classical mechanics.

than searching over all possible combinations of dihedral

2. The forces acting on each atom an.- equal to the negative gradient

angles per Se. Very fast partial optimizations are carried out for each such combination of dihedral angle ranges. Each of the torsion ranges generated by Confort brackets a single kxal minimum and is followed by energy minimization. Although still of exponential order, the number of increments used per rotor is typically between 2 and 4. thereby making

of the potential energy. 3. The potential energy may be calculated from force lields. 4. The temperature is proportional to the velocity. 5. The time average is equal to the ensemble average, which is known as the ergodic hypothesis.

the Confort algorithm extremely fast and enabling its use for searching rings and ring systems in addition to acyclic

tion, it is necessary to use Newton's laws of motion. The

In applying classical mechanics to simulate molecular mo-

three laws are summarized below:

substructures.74

Methods have been devised that alter the potential energy

hyperspace. which have been useful in locating the global minimum. Second-derivative information, discussed above. indicates the curvature of the energy surface, which may be flattened or inflated, depending on whether the surface has a positive curvature (negative second derivative) or negative curvature (positive second derivative). respectively.75 Genetic algorithms (GAs) have become popular for many applications in science, including the determination of possible conformations.76 The widespread use of GAs may be attributed to their robust nature, simplicity, and computational efficiency. One approach to the stochastic sampling of the conformational energy hypersurface uses a GA with a fitness function that attempts to select dihedral angle values leading to low-energy conformers and, possibly, simultaneously attempts to select dihedral angle values corresponding

to "diverse" conformations. Although GA-based search results arc incomplete, the energies used to "score" various conformations are calculated in an appropriate fashion.74 Another stochastic approach involves the 'poling" algorithm.77 which locates minima and artificially increases the conformational energy hyperspace until there are no minima at that location. The name is derived from the analogy of literally placing a pole in the energy well and pulling up the surface around the pole. like raising a circus tent. All methods that involve reshaping the potential energy hypersurface suffer from alterations to the surface being explored. The artificial increase in the conformational energy hypersurface near each low-energy conformation ensures that nearby con-

formations will not be selected. Although this approach is much faster than GA-based approaches, poling algorithms are often less reliable. They fail to find low-energy conformations because the conformations selected are based on artificially perturbed values of the conformational energy.

I. Law of inertia: A body stays in motion or at rest unless acted on by outside forces. 2. Fundanienial definition of force: mass x acceleration.

1- =

= ma

(Eq. 28-32)

3. Law of action—reaction: For every action. then, is an equal and opposite reaction.

= P,_, =

(Eq. 28-33)

Using Equation 28-32 as the starting point, the mass ni may be eliminated and integrated with respect to Lime I according to Equation 28-34 to give Equation 28-35, where i is the velocity and C is the integration constant. It is a simple

matter to determine the integration constant. At the initial which means that time, = 0. Therefure. the = integration constant must equal the initial velocity (C = J7.r dt dr

-

-

Jadi

(Eq. 28-34) -

(Eq. 28-35)

Integration of Equation 28-35 provides the distance a par-

ticle has traveled from its initial position i at time ito its new position + at I + (Eq. 28-36). +

=

÷ vnt + r(t)

(Eq. 28-36)

Equations 28-35 and 28-36 are known as Newton's equations of motion. MD simulations apply these two equation.s to all the atoms in a molecular structure. According to the kinetic-molecular theorem, the kinetic energy is proportional to the temperature. This remarkable relationship is shown in Equation 28-37 without derivation, where N is the number of molecules, k is the Boltzmann constant, and T is the abso-

934

and Gissvld'c Tenibook of Organic Me'du-,,:a! and Pharniaccus,eni CIw,ni.sirv

Wi/no,,

lute temperature. Equation 28-37 connects classical physics to statistical mechanics. The basic idea behind MD simulations is (0 introduce heat into the system and adjust the velocities to maintain the temperature. The forces on the atoms

can be calculated with a force field. Once the tirces are known, based on Newton's celebrated second law (Eq. 2832). the accelerations can be calculated. Using the laws of motion (Eq. 28-35 and 28-36), the velocities and new posi(ions can be calculated. This procedure is repeated for the duration of the simulation.

widely used water solvent models are SPC5' and In the former, the oxygen atom has a charge of —0.82. and the hydrogens have a charge of 0.41. The H-U-H angle is 109.5°. and the 0-I-f bond length is 1.0 A. In the latter. oxygen atom has a charge of —0,834. and the hydrogens have a charge of 0.417. The H-O-H angle is 104.5°, and the 0-H bond length is 0.957 A. To avoid potential water— vacuum interface problems that

might arise in a MD simulation, periodic boundary cotidi(ions are comnnionly used.55 Basically, a protein is surrounded by a rectangular box of water with a defined number

=

NAT

(Eq. 28-37t

The fundamental steps in a MD simulation may he summarised: I. Energy nhinimisation 2.

Elcating

3. Equilibration 4. Production runs 5. Analysis

of water structures. This water box is then surrounded on each face by another waler box. When the MD simulation is being carried out. water near the edges of the central containing the protein may leave and be replaced with a water coming from the water box on the opposite side. This procedure ensures that the waters inside the central water box remain constant. The long-range forces found in the nonbonded terms of Equation 28-19 present some unique difficulties fora MD simulation. Calculating these energy terms is CPU intensixe.

It is informative to review sonic of the information regard. ing MD time steps. It has been (earned that the best time step should be 1/10th of the largest frequency in the system. The largest frequency is associated with bond vibrations. The largest frequency = scc I) involves C-H bonds. Because the largest frequency is inversely proportional to the period of oscillation, the time step At is usually sec or I fs. Longer simulation times may be achieved

by a factor of 2 or 3 if the C-H bond vibrations are constrained. The SHAKE algorithm was developed whereby constraints are placed on the vibrations of C-H bonds.79 When calculating protein structures, one must have a good solvation model. Because water plays a critical role in en-

zynie reactions and stabilizing proteins, it is important to have effective ways to model water. In the structure-based design of human immunodeliciency virus (HIV) inhibitors, fir example. the presence of a single water molecule in the binding cavity was effectively exploited in structure-based drug design. There are essentially two ways to include solvent in MD siniulations: (a) continuum solvent models and (b) explicit solvation models. In principle, the latter should give more accurate protein simulations, but it depends highly on the water model used. The simplest continuum solvent model simply adjusts the

One early solution was to impose 8- to 10-A cutoffs. Although this saved dramatically ott the simulation times. unrealistic protein structures resulted after long runs. There were several potential workarounds. including longer cutoffs and updating these interactions beyond the standard cutoff less A very attractive approach to circumnvcn( this problem altogether, proposed by Darden. York. and Pedersen. used thc particle mesh Ewald tPME) method.55 Free energy perturbation (FEP) calculations56- '° allow direct AAG comparisons between a drug D that binds to a protein P to form the drug—protein complex D-P and a structural analogue D' and the same protein P 1 see Fig. 28-17, which depicts the free energy perturbation cycle). Determining the free energies of binding, AG1 and AG2, expemimentally can be difficult and time consuming. Converting I) into D'. and D-P into D'-P. AG.1, is experimentally fictitious. Such conversions would amount to alchemy. The conversions can, however, be curried out in silico.

D+P

tional to hr2 rather than hr. When this was first proposed. the idea was to help reduce CPU time. The rationalization is that the charges on two nonbonded atoms in a macromolecole are separated by the protein, which should reduce the

interaction erms. Thus, the interaction energy should fall off laster than hr because the charges are masked. "I

q,q, II

=

D'P

AG4

dielectric constant to equal the medium dielectric. An approximation widely used in MD simulations is known as the distance-dependent dielectric constant. In this approach, the dielectric constant is set equal to the distance as shown in Equation 28-38. The electrostatic energy is now propor-

AG,

j D'+P

D-P

FIgure 28—17 • Free energy perturbation (FEP) calculations take advantage of a thermodynamic cycle. Here, the top reaction shows a drug 0 combining with a protein P to form the The drug—protein complex 0-P with a tree energy change

bottom reaction shows another drug D' combining with an identical protein P to form a second drug—protein complex D'P with a free energy change AG2. Both of these physically observable reactions have a free energy change, AG, associated

with them. The free energy difference between the two

—

-

The other approach is to treat the solvent explicitly. There are a number of water models available.50 Two of the most

drug—protein reactions is AAG = AG2 — AG, According to the first law of thermodynamics (conservation of energy awl, the fictitious conversions, AG5 and AG.5. must be related to the experimental AAG.

Chapter 28 • C,impaua:ianal C/,e,nisfrv and Cosi,puwr-,ls.si,'aed

935

In a thermodynamic cycle. Equation 28-39 must hold. as the energy differences depend only on the initial and final

QUANTUM MECHANICS

from both sides of Equation states. Subtracting AG.; and 28-39 provides the rearranged Equation 28-40. Recognizing

One of the great theoretical accomplishments of the 20th century was the development of quantum

Equation 28-40 can be simplified = — to give Equation 28-41. This remarkable relationship, taking advantage of the thermodynamic cycle, indicates that the free energy differences based on in silico alchemy must be The method has been equivalent to the experimental used to calculate and compare the binding energies for many diflerent drug—protein complexes. Although the approach is intellectually stimulating. it requires significant computer resources. +

=

+

(Eq. 28-39

—

=

—

tEq. 28-40)

=

—

(Eq. 28-4h

Another application of interest to medicinal chemists involves the thermodynamic perturbation cycle applied to relative property calculations. For example. directly calculating the solvation of a small drug requires extensive simulation times. The drug has to transfer from in vacuo into an aqueous environment. This transfer from the gas phase to the aqueous

phase is CPU intensive, given that the solvent has to be reorganized to accommodate the solute. Calculating a second

drug analogue will involve a similar process. Making use of a thermodynamic cycle, however. can expedite the process the drug—protein (analogous to the above discussion binding). There are two types ot motion (harmonic and stochastic) that may be studied by MD simulations. Harmonic .sisnnlairons refer to oscillations near equilibrium (i.e.. near the minimum ola potential energy well). Stoelsaslic refers to simula-

tions that lead from one local minimum to another local minimum. From a harmonic oscillator, the frequencies may be calculated according to Equation 28-42. where k is the stretching constant and mu is the mass. Extending the concept from a

single mass held to a surface by a spring to N particles requires an extension of the Taylor series expansion (Eq. of partial second derivatives. 28-13) to a matrix Each mode has associated its own force constant, frequency. and 3N relative displacements. The normal modes are assigned to the experimental IR or Raman spectrum.

mechanics may be

considered weird from the standpoint of our practical everyday experiences in the macroscopic world. Nevertheless, the

applications of quantum mechanics to chemical bonding have changed the way chemists think about molecular structures and have made chemistry a subdiscipline of physics. Many unexplained chemical effects may be understood in

the context of molecular orbital (MO) calculations. For example. the anomeric effect seen in carbohydrate chemistry can be rationalized as a combination of MO interactions and

electrostatic effects. Although chemists like to follow the example of C. N. Lewis and write simplified molecular really nuclei structures (Lewis structures). embedded in a sea of electrons. It is remarkable that so many organic structures can be represented. as a tirsl approximation, by localized chemical bonds and lone pairs of electrons. As any student going through a course in organic chemistry

can attest, chemical reactivity and physical properties may be explained, in many situations, by extending our simplified bonding concepts to include resonance and electron delocalization. Because most drugs (or organic molecules) and their interactions with macromolecules are responsible for the observed biological effects called "drug action." ii is quite reasonable to usc theoretical MO methods to understand

electron distributions and predict physical properties of drug-like structures. The only way this can he achieved is through the use of quantum chemistry, since force field methods do not explicitly treat electrons. is The history of quantum mechanics, while is a full development of the theory. The goal of this chapter is to present the concepts succinctly for readers who have nevertaken courses in physical chemistry, where these topics arc more fully developed. The emphasis is on lollowing the logical order of concepts. not on the mathematical details, which means some relationships have been simplified. With the fundamentals presented below, it is possible to understand the impact quantum mechanics has, and will continue to have, on medicinal chemisto quantum try. The sections that follow contain mechanical applications in CADD.

We start with the contributions of Max Planek. At the

conlormational barriers. After the simulations are com-

beginning of the 20th century, physics was in a theoretical crisis. It was believed that Newton's equations and Maxwell's electromagnetic theory could explain all natural phenomena. but the application of thesec lassical mechanics methods to the emission of electromagnetic radiation from perfect "black bodies" did not correlate with expenmeni. In the theoretical treatments, the radiation was assumed to result Irons the microscopic oscillators, and the inescapable conclusion of classical mechanics was that a continuous

pleted, the trajectory can be reviewed. The temperature of the system can be cooled down to sample potential new conformations. MD simulations are suitable for larger molecules, and solvent may be included. No statistical or geo-

range of energies was available to the oscillator. Planck suggested in I 90() that (he energy associated with oscillators was a function of integral values of quanta (Eq. 28-43). where E is the energy of the oscillator, I, is Planek's constant (6.626

metrical means are used to determine their completeness. In general. MD simulations are not as efficient as stochastic or distance geometry methods.

worked, but many scientists of that period thought this solution was simply a mathematical trick, because the logical

I.' =

(Eq. 28-42)

MD simulations have been applied to generate new con85 The basic idea is to add enough thermal energy (through high temperatures) and carry out the simulations long enough for the molecular systems to overcome

x

10-

i-see). and u is the frequency. The suggestion

936

Wil.ron and

Texi book of Organic Medicinal and Pliannacesajeal Chenii.ur,-

extension meant that energy was available only in discrete quantum values and was not continuous.

E = liv

(Eq. 2843)

The quantum idea was used by Einstein to explain the photoelectric effect. When metal surfaces are subjected in vacuo to electromagnetic radiation of specific frequencies. electrons are released. The phenomenon could not be explained by classical mechanics. Einstein used the quantum concept to suggest that electromagnetic radiation was simply a stream of photons where Equation 28-43 correctly defined the energy. Using this quantum idea. Einstein formulated a

relationship (Eq. 28-44) between the incident electromag. netic radiation and the expelled electrons. Einstein's work supported the Planck quantum theory. In this equation. 4' is called the work function, which is the minimum energy necessary to eject electrons from the metal surface. Some simple deduction, knowing that the kinetic energy ,nt212 cannot be zero, requires that 1 = !zI'o; therefore, v0 is the minimum frequency allowed. (Interestingly, Einstein won the Nobel Prize for his contributions to understanding the photoelectric effect and related matters rather than for his theory of relativity.) liv —

(Eq. 28-44)

Because light has particle-like characteristics, de Broglie

argued that electrons should therefore exhibit wave-like characteristics. This is odd because it defies our macroscopic experiences. The wave-like character exists for all objects,

but only manifests itself—for all practical purposes—with microscopic particles (e.g.. electrons). The de Broglie relationship (Eq. 28-45) quantifies the wave-like properties that matter exhibits, where A is the wavelength. Ii is Planck's

is the momentum (mass x velocity). constant, and Clearly, the relationship shows that for tiny masses, the wave property of matter is significant, whereas for large objects, the wave-like character is vanishingly small. A = -f-'-.

(Eq. 28-45)

and lower-case chi, x. is used for a spin orbital, which is defined below.) / a2

+

a2

a2

+

+—

= 0 (Eq. 25-46)

Equation 28-46 can be arranged to give Equation 28-47. +

+ 4)

=

4-

(Eq. 28-47)

A more compact (and perhaps less offensive) form of the SchrOdinger equation is given by Equation 28-48. where —

V2 + U(x.y.z).

is understood to be a func-

(ion of the x.y.z coordinates, and V2 was defined earlier in Equation 28-26. (It is not necessary to demand that be a function of cartesian coordinates. The choice of (he coordinate system may be dictated by the nature of the problem being solved. In other words, it may be easier to solve a

problem within a different reference frame.

may be a

function of spherical polar, plane polar, or cylindrical coordinates or of other coordinate systems. For example. solution

to the hydrogen atom involves the use of spherical polar coordinates.) H is the hamilionian operator, which is the quantum mechanical equivalent of the classical mechanics formulation H = T -- U. where T is the kinetic energy and U is the potential energy. Note the similarities between the classical and quantum mechanical formulations ol the humiltonian. =

(Eq. 28—(8.i

Equation 28-48 is the Schrodinger equation for a single particle. For the application of quantum mechanics to medicinal chemistry, it is necessary to think in terms of electrons moving around nuclei. The Schrodinger equation can be con-

verted into a multiatom problem, given by Equation 28-19. In Equation 28-49. the hamiltonian is

11=

+

At this point in 20th century science, it was becoming accepted that matter had both wave-like and particle-like

The first term (kinetic energy) is a summation over all the

characteristics. Depending on the experimental setup, these

uses Coulomb's law to calculate the interaction between every pair of particles in the molecule, where e and are

seensingly contradictory properties could be observed. If matter has wave-like properties, then there had to exist some

generally descriptive wave equation. It was Erwin Schrodinger who recognized that standing waves with imposed boundary conditions yielded sets of integers, which would be consistent with spectroscopic He developed the now fumous Schradinger wave equation (Eq. 28-46) for a single particle such as an electron in a 3D box. This equation is a linear (meaning the wave function is raised to a power greater than I ). second-order differential equation

(meaning second derivatives are involved), where E is the total energy of the system. U is the potential energy, and is the electronic wave function. (Different symbols are used routinely in the literature when discussing wave functions. In this chapter, lower-case psi. cu, and uppercase psi. 'V. are used to denote the wave functions for a single particle or a multiparticle system, respectively. Also. lower.case phi, is used to represent atomic orbitals.

particles in the molecule. The second term (potential energy)

the charges on particles i and j. For electrons, the charge is

—e, while the charge for a nucleus is Zr, where Z is the atomic number. The summation notation i 4 > 3. The often-cited design of the first angiotensin-converting enzyme (ACE) inhibitors by Ondetti and Cushman during this time effectively demonstrated the concert of mecha153 nism-based and structure-based drug The Ondetti and Cushman approach resulted in the first marketed ACE inhibitor. captopril. 6 (Fig. 28-20). Many other ACE inhibitors have been designed using computer-based models.

Since the l980s. there have been many success stoties using structure-based drug design. One of the first ing examples of the combined use of an x-ray crystal

tore and molecular modeling software was reported in

OH

CH3

0

CO2H

6

7

Figure 28—20 • Captopril was the successful outcome of a

FIgure 28—2 1 • The molecule i-thyroxine, 7, binds to prealbu-

rational design approach in which the mechanism of the conversion of angiotensin Ito angiotensin II was known. The angiotensin-converting enzyme (ACE) was assumed to have binding cavities similar to the known x-ray structure of carboxypeptidase.

mm, a protein found in blood. Based on x-ray data of the thyroxmne—prealbumin complex, the binding affinity of novel analogues was predicted by using a molecular modeling approach.

Chapter 28 •

Che,nj.vrr,' cizid Con,p,,rer-Axsi.c,rd I)rsig

dimcr was unoccupied by 1.-thyroxine, 7 (Fig. 28-22). This unoccupied binding pocket had the potential to accommodate a portion of new compound. which presumably would result in greater binding affinity by increasing the contact

OH

OH

between the van der Waals surfaces in this hormone—protein complex.

941

I

The scientists used a guiding hypothesis that the "tightCO2.

ness of fit" between the computer-generated complementary molecular surfaces of the ligatid and prealbumin would correlate to enhanccd binding affinities. They modeled the mo-

8

lecular surface interactions with the MS program on an

t

...'.'

CO2.

9

Evans and Sutherland PS2 graphics station. With available

modeling software, the UCSF (University of California at San Francisco) scientists stripped L-thyroxine from the binding site and docked various naphthalene-hascd structures with different substitution patterns, shown in Figure 28-23.

The modeling studies were carried out without the aid of force held relinement. Ahier modeling a diverse set of analogues, the scientists concluded that at least three of the four outer binding pockets needed to he filled, Four thyroid

OH

O9II CO2.

hormone analogues (structures 8—11) were ranked based on visual inspection using their complementarity of fit hypothe-

sis. Structure K did not present any bad contacts, while II had some obviously bad surface contacts. Structures 9 and

10

11

10 appeared to have equally good molecular surface interac-

Figure 28—23 • Using molecular modeling methods, four

tions, Once the compounds were ranked (8 > 9 10 > II), their binding affinities were determined. The binding

finity (8 > 9

data were consistent with the predictions, except structures 9 and 10 were not equivalent. Closer inspection revealed that the phenolic hydroxyl group of 10 had a better surface fit and is in close proximity to Scr-l I 7C and Thr- I l9C. thus providing additional binding interactions not available to 9.

i-thyroxine analogues were predicted to have good binding af-

10 > 11) to prealbumin.

Presumably, the additional interactions would have been de-

tected with force field calculations. In 1985, scientists at Burroughs Weilcome (United States) and the Wellcome Research Laboratories (England) reported

some of their CADD efforts for the prediction of dihydrofolate reducta.se (DHFR) inhibitors.'" DHFR is an excellent target, since this eni.yme pathway is the only knossn de novo

synthetic route to prep-are thymine in vivo. Thymine. of course, is one of the four nucleic acids of DNA. For many years DHFR had been a popular drug target l'or medicinal chemists. Significant drug design activity using the prevailing principles of medicinal chemistry was associated with the development of DHFR inhibitors for antibacterial and antitumor agents. Methotrexate (MTX). 12. and trimcthoprim (TMP). 13. are good inhibitors of DHFR. Figure 2824 shows the obvious structural similarities of MTX and lolic acid. 14. Over the years. literally thousands of inhibitors oh' DHFR were prepared on the basis of medicinal chemistry intuition

Figure 28—22 • The experimental x-ray crystal structure of prealbumin with bound c-thyroxine. Prealbumin is a tetramer with four identical subunits. A. B, C. and D. The four identical subunits form a channel with two bound i-thyroxine molecules. The binding sites have a C2 axis of symmetry.

preceding the structure-based efforts. A series of 3'-carboxyalkoxy analogues of TMP were designed based on molecular models of the Esc/,erkl,ia coil DHFR—MTX complex. The designed IMP analogues had up to a 55-fold higher enzyme affinity than TMI' itsell'. Kuyper and coworkers noticed that in the E. eoli DHFR—MTX complex. the a- and y-carboxyl groups formed ionic interactions with the guanidinium group of Arg-57 and the aminoalkyl side chain of Lys-32. respectively. The observation that there was a possible third ionic interaction with Arg-52 suggested that TMP analogues, with judiciously selected carboxylate groups, could interact with one or more of these complementary residues. The analogue

with the carboxylate extended by five methylene units.

942

Wilson and GLvvolefs Textbook of Organic Medicinal and Pharmaceutical Chemistry

0

CO2H

NH2

N

N

Figure 28—26 • Saquinavir (Fortovase, Invirase). 15. was the H2N

first HIV-1 protease inhibitor designed with structure-based CADD methods to receive FDA approval. Here saquinavir Is shown inside the binding cavity of HIV-1.

N

was the HIV protease. The enzyme is one of the proteins coded by the HIV genome, and it is expressed as part of the reproductive cycle of the virus. The x-ray crystal structure for HJV protease has been available for well over a decade now, and it is classified as an aspartyl protease, since there are active aspartate residues present. HIV protcase is a sym. N

metric dimer. There are 99 amino acid residues in each

N

14

Figure 28—24 • Dihydrofolate reductase (DHFR) has been a popular target for drug design. Methotrexate (MTX). 12. and trimethoprim (IMP). 13, resemble folic acid. 14, the natural substrate.

shown in Figure 28-25. was found to have the optimal binding. Much of the experimental binding data were consistent

with the molecular modeling studies and the subsequent structural data. Although all the observations could not be explained, this work represents one of the first successful

monomer. The binding cavity can be seen clearly in Figure 28-26. In the late l990s, several HIV- I protease inhibitors were introduced into the market that were designed using strucHoffmann-La Roche ture-based methods (Fig. scientists used modeling methods to design saquinavirtw (Fortovase, Invirase) 15. which was the first protease inhibitor to be approved. The drug was made available in June 1995 through a compassionate treatment program. Invirase was given Food and Drug Administration (FDA) approval in December 1995, and Fortovase was approved in November 1997. Indinavir16' (Crixivan), 16. was developed by Merck scientists and given quick approval in only 42 days in Match 1996. In March 1996, Abbott received approval for Rita-

navir'62 (Norvir). 17. The following year, March 1997. Agouron received final approval for Nelfinavir'63 (Vira-

structure-based drug design approaches.

There is a growing body of successful examples using structure-based drug design approaches. Today, many of

cept), 18. Each of these drugs, designed using structure-

these have resulted in approved drugs. These methods are

based methods, represents major triumphs of CAI)D.

applied widely when appropriate experimental data are

Agouron originally was a company founded, like Vertex, on the premise that structure-based drug design is an effective approach for drug discovery. Amprenavir (Agenerase). 19, developed at Vertex, was given FDA approval in April 1999.

available. Structure-based drug design is now considered a standard approach to drug design, and the question posed early can be answered with specific examples. In the 1980s. the target enzyme for inhibitor design was DHFR. as discussed above. In the l990s, the target enzyme

The ability to collect rapid x-ray crystallographic data allowed scientists at Pharmacia & Upjohn to use structure-

NH2

NH2

Figure 28—25 • With the aid of xray data and molecular modeling. scientists designed trimethoprim (IMP), 13, analogues that had up to 55-fold higher enzyme affinity than the parent inhibitor.

ji H2N

0C113

N

OCH3 13

H2N

N

L-k

OCH3

OCH3

Chapter 28 • Conapu:utional Chemistry and Computer-Assisted Drug Design

15

943

16

OH

Cl-I3 0

17

Jo.

CONH't'Bu

18

0

OH

—

20

19

Figure 28—27 • The six HIV- 1 protease inhibitors given FDA approval between 1994 and 1999 were designed by using structure-based drug design methods.

based methods. The resulting compound tipranavir, 20. is a small nonpeptidic inhibitor that may soon be The first drug designed with structure-based methods to reach the market was dor,olamide9 (Trusopt). 1. Ab mitio calculations and modeling methods were used to predict substitution patterns. Alicr a decade of research and develop-

ment at Merck. dorzolamide was given FDA approval in December 1994 and introduced into the market in the sum-

NHCH2CH(CH3)2

mer of 1995. Dorzolamide is an effective carbonic anhydrase

inhibitor used to reduce intraocular pressures that occur in

glaucoma patients. It is extremely effective. Inhibition of carbonic anhydrase results in reduced bicarbonate fomiation in the eye. which has the beneficial effect of lowering sodium ions with the subsequent reduction of fluid secretions. Merck had been working on various lead thienothiopyran-2-sulfonamides by developing models and fitting them into electron density difference maps of carbonic anhydrase. The first car-

bonic anhydrase inhibitor to lower intraocular pressure in glaucoma patients was MK-927. which is a close structural analogue of the compound finally approved (Fig. 28-28).

21

Figure 28—28 • Dorzolamide (Trusopt), 1. also a constituent of Cosopt, was the first drug designed with structure-based CADD methods to become commercially available. MK-927. 21. is a close structural analogue and was the first carbonic anhydrase inhibitor to lower intraocular pressure in glaucoma patients

Another successful advance in therapeutics involved a combination of x-ray crystallographic studies and molecular shape analysis (MSA) to produce (Aricept). 22 (Fig. 28-29). Donepei.il is a potent acetyleholinesterase (AChE) inhibitor used in patients with Alzheimcr's disease to help stave off the loss of cognitive abilities. Docking simulations of donepezil suggested that the drug does not actually bind to the AChE active site but rather inside the long chan-

nel leading to the active Site in a tight, narrow region. In addition to the structure-based modeling studies. 3D-QSAR studies were carried out using serniempirical descriptors.

944

wul

TexiJ;rn,k of Orgw,ie sIedi,ina! anti Pliarnwteutkal CIie,ni.stri

velop a pharmacophore hypothesis. Once a phartnacophore is developed, it is possible to search 3D structural databases. The first 3D searching software was developed in-house by

pharmaceutical firms to mine the corporate 3D databases (ALADDIN.'7° developed at Abbott. and 3DSEARCH.'7'

Figure 28—29 • Donepeiil (Aricept), 22, is a potent acetyicholinesterase (AChE) inhibitor used in the treatment of Alzheimer's disease.

The pharmacophore COflCCN plays a central role in drug design. The pharmacophore. first proposed in the early I 900s by Paul Ehrlich. maybe defined as the 3D arrangement of the essential functional groups necessary to cause the biological response. The definition only assumes that it is necessary

for a drug to present its properly oriented functional groups to the receptor's complementary amino acid residues. Although the idea may he somewhat simplistic, since it ignores

explicit consideration of the molecular structure that correctly orients the functional groups, the idea has withstood

developed at Lederlc). The construction of 3D databases was madepossible by software such as CONCORD'72 and COR. INA'73 that allowed rapid generation of 3D structures front 2D structures. CONCORD has become the standard program

used for the creation or 3D structures from 2D input. It is important in 3D searches to account for structural flexibility. There are essentially three ways this may he achieved: (a) storing multiple conformations in the database itself: (I') developing specialized queries: and (E') generating conliinnations during the search query. The first idea requires that all conformations for every molecular structure be stored in 3D database. This approach is not practical. Although the second approach is appealing, it requires the scientist to sign the query appropriately. The third approach seems to solve the problem. inasmuch as only one (or a few) confor. mation needs to be stored and adjusted to match the pharmacophore search query. Today, there are several commercial

programs available for 3D database and pharmacophore

the test of tinle as a first approximation for a model of

searching.

drug—receptor interactions.

Goodford proposed that a grid of test points enveloping a molecular structure could be used to calculate favorable interactions (initially with 6—12 nonhonded, electrostatic. and hydrogen-bonding potential energy functions) between GRII)'73 was an interit and a target receptor. The program can he considesting innovation. The DOCK'7 ered the first 11mw! high-throughput screening

Prior to the explosion or structural data now available to medicinal chemists who may use 3D structures of proteins. typically only indirect inlbrination about the nature of the receptor was available. The most common situation faced by medicinal chemists was a series of active and inactive compounds. The fact that there was no structure of the drug hound to its receptor meant that drug design had to follow a procedure of comparing the efficacy of compounds and determining which functional groups were important and which functional groups were not. The active analogue approach, developed by Garland Marshall. was one of the earliest CADD pharmacophore procedt,res. 57- °" The approach avoids having to worry excessively about the subtle energy differences between conformations. Systematic conforniational searching is applied to a series of biologically active and inactive compounds. The central idea is that there is a limited set of conformations that an active compound (with appropriate functional groups) may adopt. Biological inactivity is assumed, as a first approximation, to result from the competition between small molecules and the receptor for occupation of the same physical space. Usually, the most rigid structure is considered first. Subsequent systematic searches are carried out on

the remaining ''active'' molecular structures. It is possible to add screening tiltcrs to eliminate unacceptable confornialions: for example. computer-generated structures must be able to adopt conformations similar to those available to the previous molecular structures and not be outside a specified relative energy range. At the conclusion of the process, a volume may be generated representing the union of all available conformations for the biologically active compounds.

The goal was to allow prescreening of compounds that could bind to an active site. A series of molecular structures can

be evaluated for their fit into a receptor by use of scoring functions. An early study using a.chymotrypsin ranked several known inhibitors in the top 10 structures, based on the scoring functions used to evaluate the binding potential.' Another early academic 3D searching program was CA. Predictive pharmacophore models can he generated based on 3D-QSAR analyses. Hanseh demonstrated the usefulness of QSAR.'7'> In the 1970s. many studies were undertaken to

infer biological activity on the basis of physical properties of a molecule. The method remains useful and provides valu-

able information.°'° Richard Cramer developed a popular program involving a comparative molecular field analysis (CoMFA ). "° The basic idea is to probe a molecular structure fur steric and electrostatic interactions directly, and then generate a QSAR equation based on these molecular descriptors. using partial least squares (PLS). The validity of the model can be predicted.

PREDICTIVE ADME

This "active" volume may be used to glean information

The ultimate goal of CADD is to understand at the molecular

about the receptor site. It is possible to generate an ''inactive" volume as well, which is the region in 3D space that should not be used to tuake molecular modifications. series of active and inactive compounds Examination provides important structural inflirmation that is used to de-

level the complex relationships between a target (macromolecule) and a drug-like molecule so that reli able predictions can be made to enhance molecular interac tions. Other important pharmacokinetic factors are critical. however. for an effective therapeutic medicine. Essentially.

Chapter 28 • Computational Chemistry and Computer-Assisted Drug Design potency. soluhility. and permeability are the only three physical variables that can be adjusted to enhance the activity of potential oral Lipinski has suggested "poor

absorption or permeation is likely when the molecule has more than one of the following properties."

945

electrons are involved) were carried out on a series of known drugs. The activity, defined as the AM I H-atom abstraction, is modeled on the presence or absence of chemical descriptors. Over the next decade, in silico property and toxicity pre-

dictions will increase. As the predictive methods become more reliable and robust, they will be included increasingly

I. More than 5 hydrogen hand donors 2. More than 10 hydrogen bond acceptors 3. Greater than 500 molecular weight 4. Greater than 5 computed lug P

Medical professionals must be aware of drug—drug interactions. Because a significant number of drugs are metaboli',cd by the cytochrome P-45() (CYP). it behooves medicinal

in the initial drug design process rather than being an afterthought. There are many other CADD success stories. Although drug discovery is a complex process, in the future, as our understanding of drug action increases, a growing number of therapeutically effective drugs will be designed using computer-based methods.

chemists to consider this oxidative pathway in the design process. Tragic consequences of drug—drug and food—drug

interactions have resulted in two FDA-approved drugs. nhbefradil (Posicor), 23, and lerfenadine (Seldane), 24. being removed from the market in recent years. Mibefradil and terfenadine are shown in Figure 28-30. Each drug required P-450 for phase I metabolism. A more recent predictive model for CYP 3A4 metabolism has been reported)53 The method relies on PLS. hut one of the descriptors is based on AM I-calculated hydrogen abstraction. There are several assumptions: (a) CYP 3A4 susceptibility is a function of the electronic environment around the hydrogen that is abstracted. (hi Abstraction of the hydrogen atom is the ratc-dclemiining step. (c) The drug being metabolized tumbles freely in the active site of the enzyme until the most active hydrogen is available. AM I calculations (using a procedure to account tbr the fact that unpaired

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167. Marshall. 0. R.. and Motoc. I.: Top. Mol. Ptrarmacol. 3:115. 1986. 16%. Marshall. 0. R.: Annu. Rev. Pharmacol. Toxicol. 27:193. 1987. 169. Mayer, 0., Naylor. C'. B.. Motoc, I.. and Marshall. C. R.: 3. Comput. Aided Mol. Des. 1:3. 1987. 170. Van One. J. H.. Weiningcr. 0.. and Martin, Y. C.: 3. Coniput. Aided Mol. Des. 3:225. 1989. Ill. Sheridan. R. P.. Nilakantan, R., Rusinko. A.. Ill, ci ul.: 3. Chem. Inf. Comput. Sci. 29:255. 1989. 172. Pearlman. R.: Cheer. Design Automated News 2:1. 1987. 113. Hiller. C.. and Ga.cteigcr. 3.: Fin Automatisiertcr Molekulhaukaalcn. In Gasteiger. 3. (eLI.). Software.Entwicklung in dci Chentic. Berlin. Springer, 1987. 174. Goodtord. P. J.: 3. Mcd. Cheer. 28:849, 1985. 175. Dcs.Iarlais, K. L., Sheridan. R. P.. Seibel, G. L., ci al: 3. Mcd. Cheer. 31:722. 1988. 176. Kunl:r. I. D.: Science 257: 1078, 1992. 177. Stewart. K. D.. Bentley, 3. A., and Cory. M.: Tetrahedron Cotupul. Methndol. 3:713. 1990. 118. Bartlett, P.. Shea. C. T,, Telfer, S. 3.. and Waterman, S.: CAVEAT:

A progrtitn to facilitate the structurc.denvcd design of biologically active molecules. In Roberts, S. M. (cii.). Mtiimiculur Rccognmticm: Chemical atid Biological Problems. Cambridge, Royal Society of Chemistry. 1989. pp. 182—196. 179. Hansch. C.: Ace. Chcun. Rca. 2:232. 1969. 180. Hansch. C.. and Leo. A.: Exploring QSAR: Fundantentuls and Appli. cations in Chemisity and Biology. Washington. DC. Anrcricatt Chemical Society. 1995.

181. Cramer, R. 0., III, Patterson. 0. F., atid Bunce. J. 0.: 3. Am. Chem. Soc. 110:5959, 1989. 182. Lipinski. C. A.. Lombardo. F.. Dummy. B. W., and Feeney, P. J.: Ads. Drug Delivery Rev. 23:3. 1997. 183. Singh. S. B.. Shcn. L. Q.. Walker. M. .1.. and Sheridan. K. P.:). Med. Cheer. 46:1330. 2003.

A

P

P

E

ND

I

X

Calculated Log P, Log D, and PKa values are from Chemical The log P. log D at pH 7, and Abstracts Service. American Chemical Society. Columbus. OH. 2003, and were calculated by using Advanced Chemis-

try Development (ACD) Software Solaris V4.67. The pK, values are for the most acidic HA acid and most weakly acidic BH + groups. The latter represent the most basic nitrogen. Keep in mind that pK, values for HA acids that exceed 10 to 11 mean that there will be little, if any, anionic contri-

bution in the pH ranges used in pharmaceutical formulations

and in physiological p1-1 ranges. Similarly, for BH acids. there will be little. ii any. cationic contribution for pK, sulues below 2 to 3. Because Chemical Abstracts does not leport calculated physicochemical values for ionized cornpounds including salts and quaternary amutoniurn compounds. the log P values in this appendix are for the an-

ionized form.

pK.

p11Cm

LogDat Compound

Log P

ph 7

Ahacavir Acarbose

0.72

0.72

—3.03

LogDat HA

BH 5.08

(2.39

5.90 9.11

Compound Amilonde p-Aminobenzoic acid Aminoplutathimide

239 0.34

032 0.34

13.78

Acclniainuptwn

9.86

Arninolevulinic acid

Acctazolarnldc

—0.26

—0.40

7.44

Acctic acid

—0.29

—2.49

4.79

2.24

0.03

Ace(ohydrnsaznic acid

—1.59

—1.59

9.26

Aectylcysicinc

—0.15

—3.74

3.25

Acebulolol

Log P 1.90 0.111

ph 7

HA

BH

1.8$

8.58

.58

—2.12

4.9(4

2.46

1.41

1.41

11.64)

.1.41

—0,93

—3.38

4(X)

7.37

4-Aminosalicylic acid Amiodarorar Amitriptyline Amlexunox Amlodipine Amobarbital

0.32

—3(12

338

2.21

8.59

6.29

6.14

3.98,

4,67

1.65

3,72

2.00

2.10

2.05

Anioxapine Amoxicillin

2.59

1.52

0.61

—2.21

Amphetamine

1.81

—0.91

9.37 '1.24

3.95 1.73

7.94

5.73

3.52

4.79

Acyclovir Adapalenc Ade(ovir dipivoxil

—(.76

—1.76

9.18

8.04

519

413

2.311

2.38

4.63

Amphotencin B

(1.18

3.96

8.l3

Adenunc

—2.12

—2.12

2.95

Ampicillin

1.35

—(34

2.61

6.7')

Adenosinc

—1.46

—(.46

13.11

3.25

Amprentuvir

4.20

4.20

1134

.76

Alaninc

—0.68

—3.18

9.62

2.31

Amyl nitrite

2.45

2.45

Alaurofloxacin

0.31

—2.22

0.64

8.12

Anagrelide

(.13

1.13

Albendarole

3.01

2.99

10.46

5.62

Anastrozole

0.77

0.77

Albuterol

0.02 4.26

—2.15

9.113

9.22

Anthralin

4.16

3.91

7.16

4.26

13.73

Apomorphins

2.47

2.34

9.41

Apraclonidine

1)3(1

—1.91

(.78

—5.26

5.61)

5.55

Acilretin

Alclounewsone dipropionate Alcndronic acid

—3.52

—7.80

0.47

10,56

7.59

2.03

Alkntaunil

1.89

Alltretinoin

6.83

4.62

4.79

Allopunnol

—0.48

—0.50

9,20

2.40

Arginine

—

Aripiprazole Articainc

7.9')

13.46 4.13

Asparagine

—

1.51

—4.02

2.30

834

Aspartic acid

—0.67

—4.17

2.28

9.95

Aspirin

1.19

—2.23

3.48

Astemizatie

5.80

3.62

Alazunavu'

5.51

11.11

4.81

Atrnolol

0.10

—2.03

13.8$

9.17

Alornoxetune

3.84

4.3(1

4.97

9.48

0.65

6.71

Aiprazolum

230

2.39

AIprusladli (pnataglundin E,)

2.25

2.50 0.02

Altactawinc

2.42

1.90

7.37

Ainantadine

2.22

—0.79

10.75

Arncinoniule

3.110

3.80

13.15

1,69

—4.72

1,29

10.16

Atorvastaului

4,22

(.03 134

(294

9.52

Atovaquone

8,18

4.14

948

9.11

231

1.41

—0.51

—3.84

650

—4.96

1.89

Amikacin

(.45 4.78

—2,12

0.96

—

11.7')

Ascorbic acid

Mosctron

Amifoxtine

8,93

9.94

2.44

Almotriptan

4,77

8.113

2.61

0.12

949

Appendix • Calculated Log I'. Log D. and pK,,

LogDat ph 7

LogDat HA

BH

I 2?

998

0.54

((.25

'-3.01

13.3(1

8.59

—((.94

4.181

10.32

—2.29

2.97

459

13.08

7.11

3,73

2.01

8.63

5.02

2.57

).I5 (0.54

4.27

9.2?

2.06

12.14

2.6?

12.05

(.23

(2.93

(2.67

((.56

13,89

6.07

4.30

4.54

11.49

.89

9.8(1

13.86

9.16

3.30

(3.68

8.97

11.0?

5.89

— (.34

9.63

—1.06

9.62

8.29

4.52

9.6?

6

1.30

639

6.10 3.24

12.85

—((.27

3.18

2.45

2.40

9.67

4.48

8(7 8)8

3,08

7.16

3.33

6.43

--11.52

(.52

795

5.84

7.87

6.69

-

6.72

2.93

(0.26

7.97

0.92

13.06

9.4?

-'(1.1)8

(.39

4.22

—(1.38

5.67

9.9) 3.82 13.94

carisopandol

1.0?

—3.99

2.62

—0.19

—2.7?

3.40

2.76

1.12

8.65

2.49

0.27

4.77

2.15

2.15

(2.49

1.30

10.19

1.30

4.24

7.9?

15.5?

15.5?

Caricolo?

1.67

—0.42

13.84

9.13

Carvedihol

4.23

3.16

I3.90

8.1)3

Celditorenpivosil Ccfisimc Cclonicid Crfopcrnrone

Ct(onilin

(A)?

4.81

0.97

2.67

ccradrosi?

.98

7.43

2.67

Ce(uchor

9.17

13.98

Curbanuzcpinc

carbenicilhin

BH

3.98

3.31

Cerchoir

3.97

6.12

—2.86

8.88

2.00

5.43

(1.27

Cairmustine

3.47

5.43

6.12

3.31

4.20 2.20

7.53

Caiplopril

2.5?

0.32

7.53

HA

Cup..uicin

Cnrbklopa

2.49

2.67

cilexelil

2.36

2.3?

—0.88

( 1.25-di

9.16

ph 7

Log P

Calcipou'ienc

447

(1?

0.58

Compound

0.19

—2.7?

.95

6.80

—0.09

—2.89

3.12

6.93

(.52

—2.39

2.62

—0.73

—5.13

2.80

3.27

(.23

1.13

7.57

2.89

—0.5?

—5.53

210

2.86

0.54

—4.46

1.43

2.62

—0.3?

—4.24

2.66

0.72

—3.19

2.63

2.90

Cefpodosiuncpruxciil

0.66

0.57

7.6?

2.90

Ccfpro,il

0.15

-2.67

2.92

6.93

Cc0ibuten

—1.18,

-51)8

3(8)

5.44

Celiieoxime

—0.92

--4.70

2.99

2.90

CcIiriaixonc

— (.76

—5.86

2,57

2.90

Celun,xjiiic

—0.54

—4,47

2.59

3.0?

3.0?

9.68

Ccphmkxtn

0.65

-2.22

3.12

6.80

Cephapirin

(1.79

-3.05

2.67

4.49

0.98

— (.79

3.12

6.99

Cetiozine

2.97

—(1.1)2

'L27

6.43

cesliucline

1.12

Chlorul

1.6??

—

.29

(.68

93? (0.54

Chhoruinhucj)

3.10

(.52

4.86

CII(or4mphenkol

1.02

(.02

((.1)3

3.66

2.49

2.49

-1.45

4.54

—0.46

11.73

Chkaroprncainc

3.38

1.28

9(3

Chloroquine

4.69

1.15

0.48

—0.18

—0.18

3.75

(.5?

2.07

.4?

(.4?

12.99

3.39

1.13

Chlorhesidjaic

Chhorolhizttidc Ch?orplwncsan earbaniate

Chkn'phcnirarninc

9.17 7.20

'133 (Canii,uwd)

950

Wi/son wid Gi., ,'o!d'., Texi/,ank of Orgu,zir ,l4edirinu! and I'/u:rnwc'eiuu'aI C/,c,nj.siry

pK.

Log bat

Log Dat Compound (ii(nrpiurna,Inc Chlorpropnnidc

LogP

ph7

5.36

3.01

2.2!

0.28

--((.74

—0.74

9.57 8.92

2.44

2.43

Chulccakifcrot

9.72

('ielopirox

2.59

9.72 (.76

Cilaslulin

2.42

Ciinefldinc Ciprofloxucin

HA

BH

9.43

6.25

(.6!

454

(.09

2,09

11.83

3.04

3.04

((.20

—0.11

6.73

—033

—4.58

(.3!

—(.20

4.3! 8.76 9.5')

2.74

2.89

0.41

—(.72

—7,67

2,93

0.24

0.24

(3.75

.44

Clurilhromycin

3.16

2.00

(3.07

8(4

2,78

Citalopruni Cilnc Cladnbinc

ph 7

Log P

l)ehydrncl,olic acid Detas-irdine

-764 -

Compound

1.77

—1)48

.23

—3.23

11.5$

—3.34

Dcafluruuc

1.87

(.87

Desiprrnnine

3.97

1.05

I)csli,ra(adlnc

5.26

2.95

l)cs,,hidc

-

2.72

272

csoxirnc)as,,nc

2.4(1

2.4))

Dexuincihasunc

2.0!',

2.06

2.61

2.6)

uccla(e

Dexn,cdel,,rnidine

3.!)!

2.85

I)csn,,oxanc I)cxroinehorphan

—((37

--(1.37

4.28

2.22

3.86

3.86

Diaii,nide I),hucninc I)ichl,,roace,,e acid

1.1)7

I

430

094

.07

(.95

Clasulunic acid

I.'1S

—5.84

flcma.stinc

5.69

2,83

CIi,,tbnwcin Cliuqilinni

2.14

((.4!

(2.87

8.74

1)ick,(enac

3.28

11.4$

4.32

2.35

2.10

7,24

DiclosaciIIin

3.02

—((.9!)

C1,,bclui.o1 pn)piona(c

4.18

4.18

(2,94

Dieseloininc

Clocortolonc plsulatc

4.41

13.10

Didarnn.,nc

Clirntipruminc

4.4! 7.50 8.0) 5.19

CII,JIa?epam

3.02

Clunldinc

1.41

—0.67

9(6

Cknnima,.olc

5.76

5.7!

Clozapine

3.4%

3.40

CocaIne

3.1)8

1.14

Codcinc

23.14

((.83

Colchicinc

(.03

.03

Cortisone

(.24

(.24

(2.29

('nnnolyn

(1.21)

-4.80

1.85

Croiamiio,,

3.1(1

2.42

3.10 (.83

7.46

6.22

4,06

9.2!

((.63

0.63

4319

(.69

.69

Ck,(iI7iminc

C'(.,nüphcnc

Cyclihcn,.apnnc

Cveloccrine

(.114

Cysteamine

Cysicine Cytarahine I)acuthaiine Dallopriclin

((.03

7.43

6,24

5.58

9.53 9.49

2.80

3,02

—

CyprohcpLidine 1)62

0.23

-

((.19

(3.42

I)ie(hylcarh.,Ina,ine I)ieihylpropion

3.54 (1.92

63)5

3.87

—0.92

—((93

(4

I))!)

I

2.95

(46

573

3.23

I)ifli,rusonc

2,'))

2.9!

DiOunisal

4.32

034

6.12

II')

1.14

6,33 8.97

3.02

I. (7

9.86

8.29

—0.78

(.55

I)lntcrvaprol

2.64

(1,84

0.83

118

--0,36

I

Iprosiuglaniiin El I)iphcnliydramine 1)ipwelnn

1)78

453

3.66

(.92

6.57

5.85

(.49

11.49

— .22

l)isopyniniide

(.87

1)07

4.93

8.7U

I)isiuIfir,ii,i

3.8$

2.53

8.97

1)obuiurniiue

2,49

(.56 2.40

'(.45

-

0.93

7,93

((1,47

Do)ciiltde

Delaacimn l)oiiepeuil IXfl'A

0.24

-2.3!

2.07

((.05

--2,3!)

- 2.30

13.4)!

4.47

—0.26

0.26

(2.32

4183

8.95

opauntne

—

3.88 II.) I

(1.27

2(0

4.7))

2.89

-((.23

2.73

0.12

— 2.3(i

—((.94

2.87

3.32

I)unarol

4.70

4.7!)

13.10

Danirolene

((.95

0,87

7.69

Dapipnuolc

2.44

2.2K

1,39

(.94

094

(.24

Duuxepin

5.08

2 93

2.39

((.47

8.64

I)osenalciliro(

8.15

8,14

Dapsone

I)aunor,ihiein

7.15

Dorio(uru,de

I)osaprdun

—0.2)

2 (12

3.23

2.67

(1,65

11.54

Appendix U Calculated Log P. Log I

LOgDat

LogDat Log P

ph 7

HA

BH

Compound

Log P

ph 7

2.29

0.36

7.12

14.64

Felhamaic

1.20

1.19

—0.26

—3.83

4.51)

9.32

Felodipine

4.92

4.92

7.64

7.64

9.8)

Fe,wIihr4Ic

4.144)

4.144)

4.14)

2.85

1.79

.72

—(1.56

6.85

6.85

(3.34

3.84

1.06

4.67

2.83

—1.12

—1.12

(3.66

8.23

Fciioldopam

14.146

Fcmanyl

3.93

1.90

0.76

Fenofcnadinc

5.18

2.6K

6.69

Finastcridc

3.24

3,24

Flovoxate

5.46

4.114

10.45

Flcca,nidc

3.47

0.55

40.35

Flrmuridinc

1.20

—1.21

8.9)

Flucona,o!c

5.8)

5.64

4.414)

4.85

7.92

0.56

—2.14

1.22

3.27

0.36

2.06

—0.98

2.98

—0.12

2.10

2.1(1

2.63

.66

6.1(7

1.1)5

—1.25

13.96

9.38

—0.63

--2.75

9.64)

2.2')

0,36

7.12

4.05

1.05

2,2)

—0.4)7

4.7)

4.96

1.46

3.3)

9.56

9.56

0.57

(((84

3.75

5.54)

Fludarahinc

(1.31

0.34)

—2.36

--2.38

—2.32

---2.32

1,78

(.78

Fltimacenil

0.141

0.87

9)6

Flunimilidc

2.26

2.26

8.64

Fluocinolonc

(1.77

0.77

Pluocintilonc aceionidc

2.34

2.34

Fluorcaccin

3.6)

3.60

Fliuorcxon

2,19

—3.86

acetate

8.73

Fluommethutime 7.31)

Fluoruw-ucil

Fluoxciinc

3.06

2.65

9,62

7.20

—1.28

-4,81

4.03

7.94

2.83

3.66

13.0$

8.44

Huphena7inc

2.22

2.24

—0.78

—2.29

4.35

(37

2.17

2.17

4.144

3.29

2.89

0.41

9.59

Iiumndrcn,,Iidc

1.95

(.95

1,91

—0.22

(3.88

9.17

F1,in,zcpani

4.7)

2.12

9.4(8

4.64

Flurhiprokn Flutamuk

4.11

1.28

4.06

3.06 3.92

3.80

(.84)

3.25

3.25

4.13

4.13

40.37

Fl,ilicasunc pmpicl,Iae

3.92

7,59

7,59

1(1.35

Fluva.taiin

3.72

1.01

6.62

6.62

10.35

3.17

4)86

—2.63

—7.52

5.75

5.75

3.314

—0.47

•-0.O5

—2.56

.61

F,iIie acid

Fomcpiiiik

0.714

4)714

9.64)

Formaldehyde

0.35

0.35

7.644

Furniolero)

1.57

—0.17

6.41

F,iscamei

—2,53

-7.64

Fruton,ycrn

—2.98

—7.25

2.80

7.59 5.55

5,43

432

4.52

(0.34

7.22

7.22

12.14

1.14

1.14

(4.86

0.82

1.32

4.32

—3.54

—9.2)

3.3)

0.64

3.36

3.36

4.23

4.2.2

1.97

1.96

3.34)

3.34)

4.3')

4.29

—0.0')

—0.0')

2.4$

—3.442

4.34

Fosotopril

'1.70

Fowairipian

5.84

2,65

(1.41

—4.64

0.144

—2.414,

Furnaric acid

—0.0)

—4.95

0.6K

F,,rjeolidonc

—0.04

—0.04

4.33

Fi,rowmidc

2.92

—0.84)

4.23

Gahapeutin

1.19

--1.31

3.02

Gjhintatnlnc

14(143

9.66

7,61

2(2

3.33

—2.07

—2(47

Gatitlunacin

3.59

-'(1.92

Gemeitubinc

—4)644

—0.68

Ganciclovir

'LOS

4.24

Ckm(ihr,,,ll

4.39

2)4

7.75

(Jluuepiridc

2,')4

4.27

952

Wilson and

Te.vthauk

al Organic Mt'dicina! and !'har,uaceuti,'aI C'h,',,ii.ciry pK

Compound

Log P

Log D at ph 7

HA

BH

Compound

Log P

219

0.52

5.34

1.44

—4.92

2.17

9.76

lodoquinol

4.34

—1.60

—4.1(1

2.27

952

lrinoccun

3.8)

—0.34

-0.33

lsocarhoua,id

1.03

2.70

2.7(1

3.93

2.28

luocilurinc Isofliirune

279

Glycerin

'-2.32

—2.32

1352

Glycinc

-1.03

—3.53

2.43

.64

1.95

- (AX)

12.39

111.50

('.lt,tarnic

-

(lutamine

Cslyhuride

Gnlnisein,n HCI

—2.11

11.36

Isonjucid h.oprolercnol

1.13

—0.89 0.25 —1.75

Gri'coIulvin

2.36

2.36

Gunifenesin

0.57

0.57

—1)08

—3.18

12,76

lsc*rclinoin

6.83

I .07

—3.58

13.43

lsonsupnoc

2.58

1.12

1.12

3.75

lsr.adipinc

3.68

Guunidine

2.57

0.15

9.66

Itracona,.ole

Hulcinonlde

3.32

3.32

(3.25

G,ianaderl

Gwineihidiiie

luosorbide dinhir.ne

11.81

0.90

Isocorbide mononitrMc —051

'3.3%

Kanamycin

3.29 —2.60

3.92

3.92

12.61

Kct.imine

2.15

HalofanIrijIc

11.86

6.51)

13.56

9.43

Kcloeonazolc

2.88

IlulnpcriJoI

4.06

2.80

13.90

8.25

Ketoprofen

2.81

2.30

2.30

Kctorolac

2.08

7.211

7.20

Kelolikn

4.99

—0.84

-3.68

1.57

—1.17

—0.07

—0.08

1.43

1.43

.9%

1.98

12.42

Lanoxin

1.14

Ilydrucortisone buwprule

4.12

4.12

Lansopnuolc

2.39

I.ulanoprost

3.65

Hydmcorlisonc hutyrulc

2.81

2.811

12.95

Lcflunomldc

1.95

Hydrocortisone

4.53

4.53

12.33

L.ctrouolc

3.34

3.34

12.95

propionalc

Hislurninc Hornuiropinc

Hydrnc)ikmthiaeide Hvdruconisonc Ilvdrncuutisune aCCta(C

6.58 10.15

Luhelalol

287

9.911

Lucwloe.c

—2.41

8.95

Luznivudinc

— 1.02

12.48

Lamolrig)rw

—0.19

12.10

cypionate valcrate Hydroflumelhiuildc Hydromorphond

0.54

(1.54

8.63

—1.23

—17.21

9.61

10.33

9.82

Hydmquinone

0.64

11.64

Hydroxyamphctaminc

1.117

-1.84

Hydronychkiroquinc

3.54

1.08

5.74

5.74

1.80

—1.80

2.31

2.21

Hyoscyaininc nuttü(c

1.53

—1.21

Ihuprofen

3.72

(IS

4.41

Lcucovorin I..cvalbulerol 8.36

10.71

8.87

c:IploaIc

llydroxyurea Hydri,nycinc

—

Levamisolc

6.34

0.02

054

Levuocrenol

—0.88

Lcvctirucctant

—0.67

LcvobcUtxolol

2.69

Levobirnolnl

2.86

Lcvobupivacaine

3.64

Levocahastinc

10.56

132 —8.12

Levodopu

4.86 —0.23

Levotlonacin

1.49

l..cvomclhadyl acclate

5.45

4.17

1.47

9.57

9.47

LcvonorgcuIn?J

3.92

Idai'ubicin

2.16

0,43

7.79

8.64

I.evorphanol

3.63

1f'slamldc

0.63

0.63

4.03

5.96

lnuuinih

1.86

1.18

(3.28

7.53

Lcvolhyroxine IT.,: i.'thyroxinc)

-2.78

- 5.28

4.47

10.37

Lidocuinc

2.36

Lincomycun

0.86

Iurnarnte

lmipcneni

Iiuipriirnine

4.46

2.07

lmiqntmod

2.61

0.57

Indupamide

2.111

2.09

Inditiusir

2.29

2.26

Indunicihacin

3.11

(1.30

9.49 9.04 9.35 5.73

4.17

Lindunc Linezolid

3.94 —(1.92

Liolhyronine (Ti: Irliodothyroninet

5.12

Lusinopril

1.75

Appendix • Calculated

pK. Log D at

LogP

ph7

HA

BW

054

—4.46

2.07

2.33

—0)7

2.40

2.76

2.76

10.8))

4.95

3.87

13.89

5.65

5.64

13.89

-0.95

—3.79

3.24

6.23

6.23

2.48

2.48

10.18

1)03

3.50

0.89

4.24

3.10

3,69

3,69

4.07

4.07

2,9';

2.9)

.04

—4.52

2.48

10.6')

—0.8)1

—2.38

10.16

8.58

—

2.93

2.93

-4.67

--467

Compound

1.31

(.66

8.82

Methsuxiinide

2.22

Mcthyluiopa

0.13

Methylphenidate

2.55

1.76

8.05

1.10

6.84

3.80

2.18

Methylprediusalone

2.73

4.02

3.49 6.28

Me)ipntnoto(

2.67

Melocloprwiiide

2.35

Metolzuone

3.16

MetopnAol

(.79 —0.02

13.14

4.5)

1.52

2.43

2.42

3.06

—0.02

1.66

1.33

7.06

5.02

4.83

6.73

5.91)

2.57

4.))

4.11

2.87

2.87

5.33

2.1)9

3.69

2.87

0,05

13.13

111.13

3.82

3.82

2.7)

0.22

4.50

2.40

—0 II

2.12

2.8)

1.23

2.29

—0.62

IO.38

1.85

1.81

2.04

0.93

0.70

1)70

0.73

0.63 10.29

Log P

5.02 11.35

Mexiktiiic

2.16

Mic,njtak

6.42

Mitlazolam

Midotlrine

3.67

—0.32

4.9)

3.59

— 1.40

Mllrlnunc Minocycline

0.41

—0.27

Minoezdil

(1.60

Minazapine

2.52

3.05

Miton,ycin

0.44

9.54

Mitulane

5.39

8.55

Mituxuntrone

2.62

Modalinil Monaipril

4.47

Mometasone (uroatc

4.73

2.9)

7.97

1.96

8.09 13.0')

l.4ö

Monobcnzune

2.96

0.39

(1.37

8.46

2.40

—3.13

—5.63

4.47

WOO

0.46

—2.19

.90

5.43

Monóctanoin

2.12

3.98

.45

9.66

Muntrlukast

7.85

(1.13

—2.02

9.12

9.33

2.67

0.07

— IA))

9.75

8.47

Muriclzine Morphine

2.42

2.42

12.24

—2.3)

--5.4)

13.10

Mupirocin

3.44

Mycophenolute mulch

4.10

Nohumetone

2.82

2.18

9.05

1,94

—(1.97

10.38

0.13

0.13

2.17

2.16

—0.02

—0.1)2

((.64

0.37

—2.13

2.23

0.55

0.54

(3.))))

2.4)

2.36

7.92

Nadolol

(.29

3.52

1.10

NalcillIn Naftilinc

9.26

Nalbuphine

0.33 5.28

3.54

(.27 1.97

4.2))

—0.28

—0.05

5.67-

acid

5.09

1.96

0.18

Nalumiekne

2.82

Najoxonmr

1.92

954

Wilson and Gi,wold's Textbook of Organic Medicinal and Pharmaceutical Chensisu,

pK

Log Oat Compound

Log P

phi

HA

BH

7.40

Compound

Log P

Log D at ph 7

Pantoprazole sodium

(.32

1.16

Papaverinc

3.42

3.33

Purnidehyda

0.31

0.31

Punvalcitol

5.83

5.83

Nullrexone

(.97

1.42

Nandrolone decanoate

8.14

8.14

Naphazoline

3.53

0.65

Naproxen

3.00

0.41

4.41)

Narauipmn

1.81

-—0.71

11.52

9.66

Paromomycin

Nacamycin

0.93

—1.59

3.fl

8.13

Paroxetlne

3,89

1.00

Nuleglinide

4.57

.26

3.61

Peinirolast

—(1.02

—3.12

Nedocromil

2.63

—2.37

2.00

0.52

Ncfasodone Nelfihavir

3.50

3.19

6.55

5.91

9.58

—0.31

—0.31

0.82

—2,58

(0.93 2.17

—0.11

—0.11

Nicaxdlpine

5.22

Nicotine

9.39

10.27

—3.31

Pcmoline

0.52

6.75

Penhulolol

4.17

2.05

7.53 4.74 4.82

Pctaciclovir

—2(13

—2.03

(1.93

—3.60

PenidIlinG

1.67

—2.25

Peracillin V

(.8%

—2.04

4.86

3.54 7.11

Pcntamidlnc

2.47

—0.65

0.72

-0.32

8.00

5,00

3.08

NiCtdiplne Nilulnmide

3.05

3.93

2.10

2.04

3.15

3.05 3.08

—2.82

—3.15

Nimodipine

3.94

3.94

4.01

4.46 0.83

4.46

3.91

0,37 3.97

0.37

Nlsoldipine

0.27

—035

—0.63

7.69

1.20

3.36 6.74

0.09 2.22

0.09

11.15

3.87

4.49

3.94

2.55

2.55

—1.28

—1,28

Nizalidicte

1.23

0.75

Norelgestromin

4.40

Norethiudnane acetate

3.99

4.40 3.99

Nor

1.47

Nortiipcyllne

5.65

NCvlmpine

Niucinamlde

Nicazoxanide

Nitrufurantoin Nltrofur84one

Nitroglycerin Nhrouxoxlde

0.83

'1,73

2.22

—

4.37

Olsiilailne Omeprazole

3.94

—1.06

2,7(1

1.80

9.08

Ondaautrun

2.49

1.84

Orlistal

8.95

8.94

Orphenadrlne Oselluinivir Oxacillin Oxandrolone Oxaprozln Oxazepam Oxcarbazapine Oxiconazole Oxybutynin

4(2

Olmeswmnmedosomil

4.87

Olopcitadlne

1.62

1.31

1.14

—0.22

Ptscnindamine

4.41

3.21

8.76

Plicuobarbitul

1,71

1.62

Phenoxybenzumine Plsenteroune

5.18

5.1)4

2.16 3,60

—0.56

10.08

2.27

3.30

6.74

Ptscneljino

1,03

—(35 3.20 2.26 (.86

Olanzaplne

Pennelhrin Pcrphcn5zlne Phennzopyridine Phcndimclruzine

1.44

7.33

12.47

2.1(6

Pcntmiatin Pentoxif3'lline Pergolide PcrindOpnl

10,16

2.75

Pcnicillamlnc

6.81

6.37 4.23

4.24

4.29

9.19

Phentolamine Pbenylscetic acid Pbenylephrine Phenytoin Physoutigmine

0.70 —i.\'8

—0.30

—2.20

2.52

232

1.16

—0.29

4.63

Plsyconudione

12.25

12.25

7.54

Pilocarpine Plmecrolimus

—0.10

—0.54

5.21

5.21

2.41

8.72

6.08

3.74

3.50

—0.30

8.81

Pimozide Pindolol

1.97

—0.19

2.05 3.33

—1.87

Pioglltcizone

3.16

2.40

Piperucilliri

(.88

—2.04

2,61

3.33

4.19

3.40

4.19

0.36

Pirbuterol

—(.63

—3,17

2.31

2.33

10.94

1.68

Piroxicam

1.71

—0.78

13.73

Plicamycin POdotilox

1.39 1.29

.29

Polythiazide

(.55

1,54

Pnimlpexolø

1.62

—0.77

Pranso,cine

3.51

2.95

Pravuscucjn

1,44

—1.24

1.25

(.25

5.89

5.82

5.39

3.93

11.94

Orcycodone

1,84

1.19

33.45

6.19 8.24 7.53

Occymetazoline

4.17

(3.96

10.53

Oxymetholone Osymorphone Oxycetracycline Pamldronlc.ccid

4.22 1.07

(.20 (.72 0.46

9.44)

7.48

—1.22

—4.83

430

—3.40

—7.80

0.38

9.26 8.93

4.50

Pntzouln

dnicarbata

2.44

2.44

—1,14

—(.25

3.82

3.82

Appendix I

I' Log

LogDat ph 7

LogOat HA

1.69

12.47

2.24

12.41

4.00

12.32

BH

Ritonavir

0.75

7.95

—0.25

10.38

0.84

12.26

0.06

3.69

Compound

Log P 5.08

ph 7 5.08

2.14

0.52

Rizauiptan

0.76

—1.64

1.63

.63

Ropinirole

3,19

0.81

Roplvacuine

3.11

.92

Rosglltazone

2.56

1.71

—1.43

9.86

Sulicylic acid

2.06

— .68

0.72

9.24

Sairneleml

3.16

0.97

0.11

7.46

1.34

0.29

3.69

7.82

Secoharbil3l

2.33

2.27

1.55

10.48

Sciegilinc

2.92

2.28

Serlenline

4.77

2.39

—0.59

11.30

Scvo0urunc

2.48

2.48

2.73

8.98

Sihulramine

5.43

2.88

9.31

Sildenaful

2.28

1.47

9.20

SiunvjMauin

4.41

4.41

2.39

13.82

1.40

4.16

11.00

3.29

Sirsulirnus

9.19

3.58

3.58

—4.67

—4.67

—1.82

0.99

13.84

9.14

SegnIol

0.32

.24

7.63

0.54

Sparfkcuacin

2.87

0.36

1.17

--MO

2.08 —1.25

10.61

13.96

—1.67 —0.37

--2.12

8.37

2.67 —2.35

9.38

Spimnolaclone

3.12

3.12

10.97

Stanneolol

5.53

5.53

13.91

—0.91

Stavudine

—0.91

5.06

Surcptoi.ocin

—1.55

--1.35

6.77

.Suvvituic acid

—0.59

—4.75

Suirnuanjl

3.42

2.16

Sulcnntvoic

6.03

5.90

—-0.90

—2.14

—0.12

—0.74

0.34

—0.56

3.18

—0.63

4.70

3.87

0.85

1.82

5.34

1.30

3.29

5.38

1.35

3.05

9.13

1.35

13.0$

9.13

.44

8.50

4.42

Sulfinpyraionc

2.32

—1.01

3.12

8.98

8.67

Sulliusxa,.ole

1.01

-- 1.12

0.85

3.72

5.51

Sulindac

3.56

0.80

8.40

Sumatriptuun

0.67

—1.73

6.55

Suprofen

2.42

—0.49

5.78

Tacrjruc

3.32

0.69

7.25

Tuemlimu.

3.96

3.96

Tamuxifcn

7.8$

6.20

Tamsulo,$n

2.24

0.51

Turnrutenc

6.22

6.21

—1.68

—5.68

Tc$aserod

2.19

—0.17

Tclrni.suuian

7.8(1

4.79

Temuecpuni

3.10

3.10

—0.13 1.87

2.10

4.19

3.93 6.84 2.63

12.95

—4.68

4.32

1.00

Sul08luninc

Ta,ohact,um —1.75

4.92

657

2.75

6.38

0.03

11.17

4.21

—8.56

0.32

1.88

—0.48

9.13

Temoeulomide

—1.32

Tcntporddc

3.10

5.09

Tenolovirdlcoproxil

1.97

1.97

7.91

Terazosin

—0.96

—1.0$

649

6.15

3.10

956

of Organic Medicinal and Plwrniac'euiit'al ('lwn:i.arv

Wi/ion and Gi,ii'otd '.i

Log D at

Compound

Log P

ph 7

0.48

--I .67

HA

9(2

l&onaiolc

BW 9,33

Compound 'Iriaiiicina!irnc

Log P 5.08

7.46

Tcgoswroiie enaiilliaic

2.72

7'

347

347

6.93

1,93

Triarntcrcnc

Tria,oI.iin

((.57

'Frichloroacciuc

71)3

3.49

2.23

8.24

3,3)

0,38

10,42 1.1)5

(LOS

2.87

2.86

5.05

3.98

—0.21,

—0.4))

7.44

Thiopcnlal

3(8)

2.93

7.76

Thior)du,une

(.13

3.60

'rn' 'I

1)52

Thi;ulwndazolc 'Ehio%uanine

p.

9.38

2.19

5.65

3.15

3,88

Ticiurcillin

(1.1.9

—4.3)

lickipudinc

3.53

3.21

1)45

TiinoInI

—4.30

—1.99

5.7')

5.6)

—0.33

—3.64

3.62

Tholihan

4.14

1.64

3.37

li,'anidinc

0,65

-'1.47

—3.44

—10.)))

(1.76

-1)37 I

.86

13.38

8.86 6.71

11.23

9.18 13,07

'>52 8,10

11.40

Tola,,urnidc

1.71

((.47

Tolbulauuidc

2.34

)).80

liilcap.ine

4.15

1,98

4.78

1.55

—0.98

4.46

Tollcriudine

5,77

2.80

10(8)

10.7$

Topolccun

0.79

(1.55

7.2))

2.28

Thrernifenc

7.96

6.32

Ibrcmuk

3.17

0,53

2.5)

11.4))

Truiudolapril

4.53

1.41

(1.32

—2.19

1.21

--0,56

4,06

4.06

acid Tr.uuuykyprniiulnc

Trai.odmc

(.66

1.52

Trcpro.aunil

4.09

1)47

Trelintuin

6.83

4.62

Tiiacct(n

5.06 ((.3)

TflfliCIhiilluniauiIidc

2,91

I'riuneUioPrIuiu

11.79

rrirnir.TluuTiiuic

4.8)

rr)woludinr

4.44

3.36

iropicunildc

1,16

Undecylenic iucud

3.99

.57

4.63

isupnipyl lrL.u

—2.11

Urni.duu,l

4i,6

V.uluucyc(avir

(1.4(1

V&uldccon,l.

I 44

VaI,iauicicloi'jr

0.36

Vaipruic acid

2.72

Viulujihicin

5.25

VcnI.i6uxinc (Id

291 4.9)

Vcrapamul

Tu(nafliuc

Trauuuadol

13.01

7,05

—1)51

11.86

964 944

2.62

Tiludronic ucid

u-Thcoplicml

5.11

3.80

'% —3,73

Tiopruiiin

Tnfluopcra,ine Trifluridnuc

966

3.8')

Tuocuna,ole

5.82

3.58

3.09

.67

Trickusan

7.82

—1.23

Thiothixen

2,67

8.63

3.(H

Vudaruhinc

—' I 46

Vinblaslinc

.4.22

Vuncridine

2.84

Viuiorelhiiue

542 4.3$

Vuurieorua,uilc

9.16 3.72

0.72

4.80

55)

4.9) Yohirnhuuue

1.91

(.15 8.7%

13.50

—1,51

I 00

Zuleplon 6.59

3.)')

7.alcitahine

—375

Zwuuunicir Zulcuuun

3 74

i(iOflL

—(1.24

—0.24

'I'namcinolune

1.03

(.03

11.5$

Triiurncinoluine acclurnide

260

2.60

12.69

Fijaincinolurne diacelale

.82

1.82

11.21

4.02 .,cud

'/.oImI)rlpiim Zol1iidem 7AinjsunudC

— 2.28

64 2,1,1

- (III)

a

aaa

I-

INDEX

Note: Page numbers tollowed by "r' indicate ligures: those followed by '1" indicate tables. l)nig.'. are listed under the generic ttattte.

A Abbokinase

lirokinase

AI'cixintah. 190. 634. 860) Abelcet. Ste Amphotericin I) Al' India methods. 938 Alsontlacuents, 795

Absolute ethanol. 220 Acathose. 672 Accutane. See Is,utretinoin

ACE. St. Angiotensin-converling enzyme Acehatolol. 544 -545. 5451 ACE inhibitors .Ievelopntent of. pruidnig loans ot. (v46-M%, 6471, 647t Acellular vaccines. 2(17-208 Acetaminophen. 76 Ii. 762. 822 aracltidonic acid metabolism and. 822 mecltanisnu of action ol, 822 metabolism u,1, '16—98, 112. 115. 120 Acetanilid. 76(1, 7611, 762 Acetan.ulatnide. 64)3. 6041. 605. 619 Acetohevantide, 668, 669-674) active tneta)xul,tes a), I 35t metabolism 1,1. 82. 103— lOS Acet.tphenone. memabolisut ci). 1113 761t, 762

Acetosyedtyl uuttium '.alt'. 557t Acetoxyphenylmetcttry, 23(1 2-Acetylantinotluomene I AAF) metabolism o1. 96 toxicity or, 115—116 Acetylatiu'n. in drug metabolism. 12) — (24. 4231

mciaUcdinic differences in. (24 Acetylation ,xtl) mturphmistuu. 122— 124

Acetylcholine )AChl. 548 coaliunuation of, 34—35, 341, 555-556 ganglionic stimulation by. 5871 hydrolysis a1, 561—563. 561t. 562). 5631 tunscarinic receptors and, 550. 551. 552. 557—55%. 5571. 557t

netirotttttscular jancluon transmissi,un and. 589

as neurotranstttitter. 548. 551). 551, 552. 557—558. 5571. 557t. 586—588. 587) nicotitutc effect of. 587—588,59(1 phamiacetnical. 558 release iii, .5531. 554. 683 storage of. 5531. 554 structure—activity relationships for. 557- 558 structure of. 55(1 syn)hes.s of. .553—554. 5531. 5541

Acetyl-CoA. 55 554. 5541 tn drug metabolism. 122 Acetylntcthadol. active ntetabolites iii. 135t metaholisttt of. 124 Acetylsalicylic acid. Sn' Aspiriti Acltrontyctn See Tetracycline

Adapin. Ste Doxepitu hydrocltloride Adaplive ittttttanity. 2(11), 2)88 Adaptogen. 913 A,ldictiutn liability. 732 Addisons disease. 8)0

Acid(s), 9—17

Adenosine. as sleep-promoting agent. 48% Adenosine arahintusi,le. 376, 405. 408 Aclentusine deamina.se inhibitors. 40% Adenosine ntonophuspltate )AMP), 551. 553 it, snuctoth muscle relaxation. 623—624. 624f

1311

)ionieed), IS—lb. 161

crunjugate. 9 delunitiot, cut. 9

examples of. 1(8

IIA )unionieedt, 15-16. 16t ionic form iii. IS—lb. (5). 161 pH of. calculation 'if. 13

S-Adenosylituethionine )SAM), in ntethylation.

pK, ol. 13—14. 14t

A[)MET properties

125. 1261

Adenylute cycla.se. 553

strength of. II — 14 Acid—base balance. 3

defiutitiout of. 54. 61) screening for. 54

Acid—base reactions. Il—IS. 12t direction of, 13

l.ipinski Rule of Five for. 40. 54

Ac.d—ccuntngate base. 9—Il

Actpbes See Rabeprazohe sodium

Acitretin, 874 hall-life oh. 6 Acivicin. 421) Aclacunontycin A. 416 Aclanthtcin, 416 Aclometasone dipriupionate. 8081. 812 Acl,usate,S,'r Actattietas,,ne dipropioutate Acquired imtuunity, 2(11). 2(Xlt Acquired itttmunodeliciency syndronte. See Human itntttttttodeftciettcy virus Acrivastine, 714—715 Acrodynia. 891 Adrenocorticotropic horntoite AC'l'H

A(TH S,'. Repositcury corticotropiit injection Actbar.S,,' Coriicoto.pmn injection ACTH injection. 842. 842t Acthrel. See Corticorelin Actidil.S,',' Triproliditte hydrochlutritle Actinttttutte.Su'.' ltttrrferon gammaS lb Actinomycin C,. 414. 415. 421—422 Aciinomycin C,. 415 Actinomycin I), 414. 415 Actiutomycins. 3486. 414—415. 421—422 Action potential. 68(1—681, 683 Acttvase. See Alteplase Active analogue approach. 944

Activella.S,'e Hormone replacentent therapy Active-site—direcled irreversible inhibition. 29 Active tabular secretion. 60) -602, 6021

Acetylcholine chloride. 558

Aetcus. See Pioglitazone

Acetylchohine receptor. 549—551). 684—685 Acetylclttuhinc.ster.tw (ACIIEI. 54%, 553—554, 5531. 5541,56)1—561. 561t actiuun of. 561—563. 561t. 5621. 563t

Acaretic. See Quinapril Itydrocltloride Acute phase prtuteins. 21)). 201t Aeyclosir. 377

phosphorylalion iii. 568. 56Sf reactivation of. 5681. 569 Acety)cholittestcrase inhihitoo,563—569. 563)

Adenoltypopluysis. 1141

Acyla.scs, 306 Acylureudopeiticillins. 3118

Adalat. See Nifedipine Adapaletue. 874

prediction of. 944—945 uI recotttbinattt drugs. 175

virtual (in silico) scrcening for. 55. 9(9 Adrenitl cones horm,,ne,s. 803—815.

,,fsr,

(ilucocorticoid(s): Mineraloconicc,id)s I Adrenaline. 67%. See also Epinephrine Adrenergic agenis. 524—546 centr.tIIy acting. 652—653 definition oh. 52.1 sympatholytics. 524 sytttpadtotttimetics. 524 Adtenergtc-hhux-kung agents. 524, 651—652

Adrenergic nettrotr.tnsmittcrs.524—547 biosynthesis of. 524—525. 5241 properties of. 524 receptors for. 527—528 structure 01, 524 a.s symnpatttuumimetics, 532

uptake and nuetalxulistut of, 525—527. 5261 Adrenergie receptuur antagonisus. 539—546

a. 539-544) 541-546 Adrenergic receptturs

a. 527-52% 528

heterogeneity of. 169-li)), 171* Adrenergic stimulants. 524 Adrenergic system itthibimors. 649—650 Adreutoconicotropic Itonnoute )ACFH). 8(15, 841

biological activities of. 841 hydrocortisone and. 806 products. 842—844. %42t structure—activity relatuuunships for. 841 Adriantycin. Ste Donomuhicutu

Adriamycinol. 416 Advi). Ste Ihuprofen AenuBid. St.,' Fluttisuulide Aercu.sporitu. See Ptulymyxun Ii sulfite

Affinity chnumatography. in receptor isolaticuit. 2%

Ahiatosin I),. hepatuucawinogenicitv 'if, 76—77

957

958

Inde.s

African sleeping sickness. 260 Afrin. See Oxymetazoline Afnnol. See .1 + ).Pseudoephedrine

Alkylation. 394—398, 396—3991 biorcthtctive. 397

Agonism. inverse. 4115

by conjugalc addition, 397 definition of. 394 by free radical reactions. 397 mechanisms of. 394—398. 396f—399f reaction order in. 394 Alkylbcnzyldimethylammooium chloride. 225 Allegro. See Fcxolenadine Allergic rhinitis, 813—815

AIDS

Allergy

Autate, See Tolnut'tate Age. sirug metabolism and, 126—1211 Agenerasc Cr Aniprenavir

Agglutination, in immune response. 205 protein. 175 Aglycones. 417 cc Human imnsunodcficiency virus infection Akineton hydrochloride. Btpcridcn hydrochloride Alamust. See Pemirola.st potassium ophthalmic solution Albamycin. See Novobiocin sodium Albcrtdaaole. 266 Albumin(s), 8331 drag binding to. 6 Albuminoids, 8331 Albuterol. 536 Alcohol. 219—220 dchydr.tted. 220 intolerance to. cephalosporin.eclated, 325 mechanism of action of, 6114 Alcohol dehydrogenace',. 1(11

Alcohol promoictv. for prodrugs. 144—149. 14Sf— 149f

Alcohols as anti.infec(ivc agents, 219—221) carbamate derivatives of, 495—4% glacuronidation of, 112 oxidation of. 99—101 as sedativc.hvpnotirs. 495—4% Aldactaiide. See Spirisnolactoneltydrochlorothinzide Aldactone, Ste Spironolactonc Aldehyde carbonyls. metabolism of. 103—1117 Aldehydes as unti-intectives. 220—22) metabolism of, 99—101 as scdntise.hypnotics. 220—221 Aldeslcukin. 182—183,441—442, 859t. 1162 reductases. 103

Aldomet. See Methyldopa Aldomet ester. See Methyldopate Aldomct ester hydrochloride. Sec Methyldopate Aldophosphamide. metabolism of. 95—96 Aldosterone. Sec aI.vo Minentlocorticoid(s) analogues ot', 806—809. 806*

biological activities of. 805 biosynthesis of, 7691, 770. 804—805, 11041 excess of. 805

extrarenul actions of, 6)9 relative activity of. 809t ctnlcturC of. 807f Aldosterone antagonists. 6(9. 815 Alenttueumah. 189 Alfenta. See Alfentanil hydrochloride Alfcnionil hydrochloride. 748 Alferon N. See Interferon alfa-n3 Alida,se. Sec Hyaluronidase for injection Alitretinoin, 874 Alkaloid local anesthetics, 690 Alkcran. See Melphulan Alkylating agents, 394—102. See also Anlincoplastic agents activation of. 395—39*. 3961—3981

discovery and development of. 394 drug products. 399—402 mechanism of action of. 398—399 metabolism of. 395—396. 3')6f properties of. 394—399

toxicity of. 399

aspirin. 820—821

to cephalosporins. 325 to contrast agents. 481 to local anesthetics. 689—690 to pcnicillins. 308—309 .4 Ilium .ca:it'unt (garlic), 910—911

Allopunnol. 405. 414 All.or.notlting law. 680 Allylamine antilungals. 238—239 Ally) chloride. toxicily of. 1111—119 Allylisopropylacetamidc. metabolism oF. 77 Alomide. See Lodonamide trometitaminc Aipha-aslrenergic receptor antagonists. 539—540

Alphacetylmethudol, 738. 7391 Alphagan. See Brimonidinc

Alpha.paflicle emission. 456 Alphnprodinc. 736t. 737. 747—748 Alphaxalone, 488

Alprjiolam. 492 Alprostadil, 827 Aires. See Loteprednol etubonate Altace. Sec Ramipnl Alteplase. 184. 1841. 841). 859*

Altretamine. 429. 432 Alsipent. See Metaprolerenol Aluratc. See Amoba,bital sodium Alveolar nsacrophages. 198. (99* AM) method, 938 Atnantadine. 372—373

metabolism of. 92. 93, 126 Amaranth, metabolism of, (07 Atnaryl. Sec Glimepiride Ambenonium chloride. 565 Ambien. See Zolpidem AtnlSisotne. See Amphotcricin B Ambodryl Hydrochloride. See Beomodiphnnhydramine hydrochloride Anscill. See Ampicillin Amcinonidc. 8081. 812 100. 387 Amebiasis. 259—260 Amethocaine. 690-693. 6911 Amrthopterin. See Methotrexate

AMI.25. Sce Ferumoxides AMI.227. See Fenimoxtran Amidate. See Etomidate Amidec hydrolysis of. 109—110 metabolism of, 94—98 Amidopynnc. 7621. 763 Amifostine. 445. 446 Amigesic. See Salsalate Amikacin. 339—340 inactivation of. 336 Amikin. See Amikacin Amiloride hydmchlonde. 617—618. 620 Amiloride.hydrochlorothiazide. 620 Amines utietbylalion of. 12.5 prodnig forms of. (49. 1501 Amino acids, separation and identification of, 834

Amino acid sequences. 162 databases of. 39..40

Antinu acid solutioto. 830—831 Aminoalcohol esters, 579—582, 5112—583 Aminoalcohol ethers. 582—583

Aminoalcohols. 583—584 Aminoalkyl ethers. 702—7(44 Aminoamides. 584—585

p-Aminobenzoic acid (PABA). 901 metabolism of. 22. l23f in sulicylate preparations, 755 'y.Aminobutyric acid. 485. 489 receptor for. See also GABAA, receptors Aminoglutethimide. 784. 7841. 785 Aminoglycosides. 334—341

chemistry of. 335 mechanism of action of. 300*, 302. 335 microbial resistance to, 335—336 potency/toxicity ratios for, 337 side effects of, 335. 337—338 spectrum of activity of. 335 structure—activity relationships of. 336—337 structure of. 335 types of. 337—341. 341 $-Aminoketoncs. 501—502 p.Aminophenul. 761t, 762 Aminophenois, 760-762. 761t Aminopyrine. 762t. 763 Aminosulicylate sodium, 256—257 p-Aminocalicylic acid (PAS). 254. 256 metabolism of. 122. l23f Amiodarone. 641

Amitriptyline. 517 active metabolites of. 134. 135t metabolism of, 77f Amlralipine. 631 Ammoniated nietcufy. 22* Antobarbital. 494. 494t metabolism of. El Amobarbital sodium. 494, 494* Amodiaquine. 287f. 288 Amoxapine. 518 Amoxicillin. 309*, 313. See also Penicillin(s) Antonicillin-clavulanate, 316

Amonil. See Amoxtcillin AMP (adeno.cine monophosphate. 551. 553 Atophetamine. 512. 513 metabolism of, 70. 91, 92, 106—107 species differences in. 128 Amphicol. Sec Chlor.ttnphcnicol

Amphocil. See Amphotencin B Amphocyte. See Amphotencin B Amphotencin B. 236—237. 300t Amphonaic substances. II Ampicillin. 309L 312. See also Penicillints) allergy to. 309 extended activity oF, 307 prodrug form of. 143-144. 1441 spectrum of activity of, 307. 323 Atnpicillin.sulbactum. 316 Amprenavir. 385—387 development of. 942. 9431 Amrinonc. 656—657 Amsucrine, 429

Amyl nitrite. 625t. 626 Amylocainc. 678 Amytul. See Amobarbital Anabolic androgenic steroids.

Androge*s) Anabolin. See Nandrolone decanoate Anadamide. as sleep.promoting agent, 488 Anadml. See Oxymediolone Anafrunil. Set' Clomipramine hydrochloride Analeptics. 510—511 Analgesic udjavunts. 731. 732 Analgesics. 731—763 anti.inflammattt,ry. 753—763. Sec also Antiinflammatory analgesics

I,idt'x

dCfinhliOfl of. 73

development of. 940 prodrug forms of. 646—648, (i47f, 6471 Angiotensin II blockers. 648—649

dependence liability nI. 732

Angiolensins. 856

discovery and development of. 731,

Anhydron. See Cyclothiazide 5.6.Anhydrot.elracyclinc. 343. 3431', 344 Anileridine, 736t, 737. 748 Aniline. 2711. 760. 7611 tnctitbolistn of, 93, 122. 1231 Aniline derivatives, as local anesthetics,

classes iii. 731. 732 coal tar. 760. 7611

732—741

historical petspeclise on. 731 morphine and related compounds. 731—753. See uIso Morphine and related compounds receptor interactions with. 741—744. 7421. 7431

stnlcture-activity relationships for. 741—744. 7421. 7431

underutiliialion of. 731 —732 urinary. 253-254 Analgesiophores. 742—743

Analogue inhihitors. 384 Anamnestic response. 205. 2051 Ananase. See Bromelains Anaphyluxis.Sce Allergy Anapron. See Naproxen Anastroiote. 437—438, 71(4—71(5. 71(41

as antineopln.slic. 435

Ancef. Set' Cefazolin Aitcitabine. 407—408 Ancobon. Set' Flucytosinc Androgen(s). 797—1103

as antincoplastics. 434 athletic perforniance and. 800

biological activity of. 797. 798t biosynthesis of, 7691. 770, 7741. 775. 797. 7971

endogenous. 797

liepatotoxicity of, 798 metabolism of. 797, 79t)t products. 11(8)— 1(01

semisynthetic analogues. 798—799. 7991 side effects of. 799—800 structural classes 1)1. 798. 7991 structure—activity relationships for. 798—799. 7981

therapeutic uses ol, 799—8(8)

virilizing effects ol. 799—800 Androgen receptors. 773 Androslenedione biosynthesis of. 7691. 770 conversion ol to eslrone, 783. 7831

Anertine. See Succinylcholine chloride Anemia hypochromic. 1193 pernicious. 895 Anesthesia

cataleptic (dissociative). 488 cpidur.il. 6117

field block. 687 general. 485—488 inhalational. 486—487 iniraventius. 41(7—488 infiltration, (i117 intravenous general. 487—4118

regional. 687 local. 676—694. See also Local anesthetics in spinal anesthesia. 687 topical. 687 Anestltesine. Sit' Benzocaine Angina pectoris. 622 Angiogenesis inhibitors, 447 Angiography. 418—479. 4191 Angiotensin amide. 856 Angiotensin.converting eneynte. 856 in blood pressure regulation. 644—645, 6441. 6451

Angiotensin.converting enzyme inhibitors

690—693. ft92f. 1i92t Anilines. hydioxylated. 7(10—762 Anisidine. 7611. 762

Anisindionc. 668 Aninoactinomycins, 415 Annihilation radiation. 456 Anoilynes. 752 Antiplti'les mosquito. 282—283 Ansaid See Flurbiprofen Ansamycins. 257 Anspor. See Cephadrinc Antalgics. 753 Antaioline phosphate. 7(14. 706 Antergen. See Phcnbcnzamine Anthelmintics. 264—267 Anihi'mi.i (chamomile). 911 Anlltrucyclines. 415—417 Anthrucyclinnnes. 41(1 Antiadrenergics. 524 Antiandrogens. 801—802. 8021 Atitianginal agents. 622—633 Antianbythmic agents. 634—642 class I lmcmbranc.depressant). 636. 6361. 641

class II 4$-blockers). 6361. 637. 641

class Ill lrepolnxitaiion prolotigatots). 636u. (i37. 641—642

class IV (calcium channel blockers). 6361. 637. 642 pH and activity of. 637 types of. 637—642 Antibacterial antibiotics, 299—364. See also

Antibiotics synthetic. 247—252

Antibiotics aminoglycoside. 334—341 antibacterial. 299—3M synthetic. 247—252 antifungal. 235—238 antineuplastic. 414—424. Set' also Antineoplasuic agents, antibiotics antitubcrcular. 257—259. 338. 339 fl'lactain. 301—314. 301 —334. See also

Cephalosponna: Penicillin(s) fl.lactatnasc inhibitors. 314—318 hroad.spectntm. 3(1). 323 cephalosporins.3 18—334

chemical classification of. 301 conititcrcial production of. 300 current status of, 299—3(11)

definition 01. 299 discovery of. 299 historical perspective on. 299 (incumycins. 353—355 macrolide, 349—355 mechanism of action of. 3111—30!, 3118 niicrnbial resistance to. 301. 305—307. 335—336

monohaclam, 334 polyene. 235—238 polypeptide. 355—360 properties of. 299—300

spectrum of activity of. 300 structural diversity of. 301 teuucyclines. 341—349

959

unclassified, 360—3M uses of, 30(1 Antibodies. 2112, 21)3—2114. 21131. 21141. See alai.

lmntunoglobutin(s) attlino acid sequence of. 204. 2041' antigetis and, 205—206. 2051 complcmentunty.deterntinitig regions of. 188 human 442 hypervariubte regions ot. 188 tuonoclonal. 187—191 as anlineoplaslics. 442—4.14

chlmcric. 189 diagnostic. 470 preparation of, 187—189. 1881 in radionuclide test kits. 190— l')l

therapeutic. I'll types 01'. 189—191

pol>clonal. 87 production of, 204—205. 2051 structure itt', 203—2)14, 2041. 443. 4431' types of. 2116

Anticholinergics. See Cholinergic blocking agents

Aitticoagulants. 663—668 endogentius. 664—665 recombinant. 185

ani, conlonnation. 32. 33 AnticonvulsanLs503—5t)l( barbiturates, 504 bene.odiazepincs.Sttl—5l)8 ttyduntoins. 5(14—5(15

iitiscellatieous. 506—54)7 mintoacylunsas. 506 oxazolidittediones. 51)5 structure—aclisily relationships for. 51)3—501 succittimides, 505—5(16 ureas. 51)6 Atittdepressants, 5111

nietabolism of. 87 monoamine oxidace inhibitors, 514—SIft. 5151

inonoatitine reuptake inhibitors. 51(1

nonselcciis'e 5-I'll reuptake inhibitors. 519 selective norepincphnne retiptuke inhibitors, SIt) selective serotottin reuptake inhibitors. 518—5 9 tricyclic. 516—519 Antidiurelic hormone. Set' Vasopressin Anhiepileptics. Set' Anticonvalsants Antiestrogetis. 711—7112. 7811

Antifungal agents. 230—246 allytamine. 238—239 antibiotic. 235—238 azole. 24(1—245. 2411'

historical perspective on. 2311 nticleoside. 235

topical. 233-235. 239 Antigeti(s) cellular, in vaccine production. 207 major hlstocompatibitity. 197 Antigen-antibody reactions. 21)5—2)11,. 20Sf Antigen.prevenhing cells. 199. 1991

Antiltetnopllilic factor. 664t. 6(15. 863 reconthinant. 167—168. 1114—185. 665. 8591. 663

Antihistaminec. 700-715 dihenzocycloheplanes. 711—712. 1121 dibeneocycloheptenes. 711-712.1121

discovery and developnietit itt. 700. 71)1—71)2

drug interactions with. 7(12 dual.uciing. 717—718 ethanoluntine. 7(t2—104, 7(121 ethylenediamine. 7)14—706, 71)41

960

Indc

Atttihtstamincs (.onhintwd)

tico-generation (cla.ssical). 7(81—712 index

alkylating agents. 394—4)12. See alsi.

Alkylating agents

br, 7(11)

indications (or. 701 mast ccli stahilicers. 715—717 mcchattisttt of ai.'tic,n of. 7(X) tuetabolisin ot', 87 tton—targct.rcceptor interactions of. 701 pharniucokittctics of, 71)1 —71)2

pltenirumine. 707-7))) phenothiaiittc. 71)1—711 pipcr.u.inc (cyclwinc), 7(16—71)7, 7061 propylaminc. 707—710. 7071 second-generation Iflonsedating). 71)) —702. 7(2—7)5 relationships (or. 7(X)—i))?

Antihypcriipidcmic agents. 659—663 HMG-CoA reductase mhihitors, (,62—(i63 Antiitypcflensive agents, 642-657 ACE inhibitor prodnigs, 646—648. 647)•.

(slit adrenergic system inhtbttors. angiOtensin antagonislc. 6411- 649 cenirully acting adrenergie drugs. 652—653 neun ansn (cr-depleting. 650-4,5) positive inotropic agents. 655—657 ptltassinni channel openers. 654-655 renin-angiotettsin system inhibitors. 645—646 selective o.adrcncrgic antagottists. 651—652 vasixtilators. 653—654 Anti-infective agents, 2)7—2111) classificalion of. 217—2111

germicidal. 217-218. 2)16 historical perspective on. 2(7 selective tosicity 217 Anti-inflammatory analgesics. 754- 763 p.aminop(tcnol. 760—762. 76lt aniline. 760—762. 7611

aracltidonic acid metabolism attd. 822 arykicetic acid derivatives. 758—764) N.arylantlira?inic acids. 754—758 mechanism of action of, 8(8, 822 pyruiolidincdionc derivotives. 762—763. 76)) pyra,.olonc derivatives. 762—763 salicylates. 754—757

Antileprutic agent,. 27')—28(t Antitnalarials. 2112—298 4.atninoqtiinolones. 287—288. 2871. 2951 8-itmimx3uinolones. 288—289. 2891, 2951

cincliona alkaloids. 286—287, 2861. 295t

of, 28)

angiogenesis inhibitors, .147 antibiotics. 414—424

actinotttycins, 414 -4)5 antltracyclines. 415—417 discovery and developmctit of. 414. -115 ntedtanisiti of action of, 415 structure ol, 414—415 atttintctabolitcs. 402—.1l4.See of*., Antimetabolites antiscnse oligutners. 447—44%

aureolic acids. 417 hiotecltniilmmgy and. 4411.449

cattcer curability attd. 390 candidates for. 4.16—449

cell-cycle speciticity of. 39), 3911 clinical trials of, 394 itt conthination ttterupy. 390 cytoprotcctivc. 445—446 cytohmxicity nt. 390. 391 discovery and dcvelmsptnenl ol. 392—394

tirst-ordet log-kill Itypotitesis kit. 39) hurtttm,nes. 433-4)8 inmtunotherapentic. 340—442

labeliitg ittdex lot. 39) mechanism of action of. 390 mottoclonal antibodies, 442—144

overview of, 39)) plant products, 424—428, 9)5 platinttttt 428 prodrug. 156—159 radiotherapctttic. 444 -445 receptor tyrosinc kmnase mn(ithitors. 438-44(1 rescareh directions ('or, 446—449

resistance o,.392 screetting of, 392—394, 39))' signal transductiott itthihitors as. 438—440 site-specific delis-cry nt. 158—159 telomcr.ose inhibitors. 448, 441ff

tonicity iii. 392

2961

formulations ol, 285—298 in glucose-6-phosphatase dehydrogenase deticiency, 283 indications for, 295t—296t

of, 284-285

polvcyclic. 293—294. 2931. 296) fur prmmphylanis. 295t—296t

selective toxicity of, 285 fur treatmenL 295t—296t Antimanic agents. 503 Antimetaho)itcs. 41)2—.) Id activation of, 402—411

definition iii, 402 de novo synthesis of. 4)12—404, 4031—4041

development of, 404 dnig prmmdttcts. 411-414

tnechanicm of action of. 402—404 Antiminth. Sr.' Pyrattic) panloate Atttintuscarittic agents. Si-i' Choltnergic hlneking agents

Antitoxin. 2(17 Atttitubercular agents. 254 —259 antibiotic, 257 —259. 338, 339 Antitttssives. 752—753 Ant juIcer agents chetttical cotnplen&ttion of. 726 Itistarnine I-I. inhibitmirs. 71(1. 718- 722 pnistaglamtdins. 726

protott pump inhibitors. 722-726. 723f—725t. 723t Amttivert Sos' Medicine hydimidmlminile

Amttiviral agents. 375—388 analogue inltthitors. 31)4 himi.tctixation of, 135. 1351

hinclientical targets lor,370—372 cliettti,kine receptor bitiders, 387 des-elopment of. 370 DNA inhibitors. 372, 375—379 gp4l fusion nctivmty inhibitors. 387—388

WV entry inhihibirs. 387 lily pn1)easc inhthiturs. 384—387 deselupntetmt of, 942. 9431' intcgrase imt)tibito,rs. .188 ototnetmclature of. 372 iti,nnticlco,oide reverse tr.mttscrlpma.se

in(tihitors. 383—384 nucleoside antintettobolite,. 372. 375—382 as prodntgs

activation oiL (53-- 154. 15Sf in chemical detisery. 157 resistance to. 3(12 reset-se trunscriptasc itthihitors, 372. 379—381. 382 types of. 375—388 Anxio(ytics. hypitotics. and cedatises, 485—4% alcoltots, 495—496 barbiturates. 493—495 beitrcnliouepines. 488—493

tttiscellaneotis. 495 overview of. -(85 structure—activity relationships liii. 489—48) Apoilopoiprootcitis, 657

tutloor cell pnipenics attd. 39)4—394 Antittuelear antibodies. acetylation po)%-tttorphisttl and. (24 Antipedicular agents. 268 Antiplatelet agen(s, 632—634 Antiprotocoal agents. 259—264

Antipsychotics, 496 -5(t) 51)1—51(2

atitmmttattic agents. 5113

dosage of. 295i—2%t lined-combination. 289—292. 2891—2921.

mechanism of actiott new. 294—298. 291mm

Atmtineoplastic ;mgents.39))—449

atypical. 485. 49)1 beneamides.502—503 llttorobutyropltettoncs. 5(K)—SIt I mechatmismmt of action of, 497

phettotlttacines. 498-5181. 499t typical, 485. 497 Antipyretics, analgesic of. 753.5cc also Attti.inIl.mtnmatory analgesics Antipyritte. 7(,2. 763. 763t Atttiscahious agents. 268 Antisecretory agenls. 573—574 Antiseirtire agertis. See Anticonsulsants Aittisense uligoniers. 447—448 Antisetmse RNA. 193— (94 Atttmsense technology. 193—194 Antiseptics, 217—218. 218—223. 218t classification 0), 2(11, 21 Ill

el fedisetiess oil, evalitatioti of. 219 intpropcr tise ol. 219 plicitol cueflicicnt l'or. 221

Apottiiirphine ltydrodtlormde. 747—7411 Apupnitein. itt cytochrmutie P451). 67 Apoptosis. 39(1—39) Apr,tc lottidone. 534

Apresoline. Sic I-Iyolralaiitte Aprohart,ttal, 494, 4941

AqtIaMIiPHYTON See Phytonadione Aquaphor Sec Xipatnktc Aqtiasol A Sos' Vitamin A. L'SP Aquatensen See Mcthyc)ot)tiaiidc Clopamide At-a-C. Scm Cytar.thtnc

Ar.tchidontc acid. 4,66,818 tttclabotistii or. 82)1. 822 Arachidonmc acid cascade. 818, 8)91, 82)))' Ar,tleio. See Chtoromquitic

Aramine Soo' Met.or'.,mini,l Arcitutitottm.mh.

94)

Arduan. Sri' l'ipccunumn bromide Arecoline. 558 Arenas. oxidatioit ol. 74. 7)11, 72). 74f Artunnd Sc.' l'nntethaphon catitsylate Aribofloivimtosis. II'))

Aricept Sic Doneperil Ari,nidex. Aromasin Se.' Aroittiatase inltihitor'.. 783-785. 7831. 7841 Aruitiatic .itnines 01. 93

Atttithrot,tbitt Ill, 665

of, 93 Arontatic loydnocarbnlmi.s'arcittogctticit) (it, 7'

Antithrontbotic ngetmts. 632—634 Atttithyromid agents. 673—674

Aronm.ttic hydruvylution. 69- 74, 7111. 72). 74i

Antospasmodics. S73—574

metabolism 741'

lusdtts

Arrhythmias. 634—636 Arsenic Irtoxide. 428. 432 Arsohal. See Melarsoprol

Arlane. Sec 'lruhesyplienidvl bydrochlonde Anemisimn, 294—297, 294), 296t Aflcriogr.tphy. 478—479. 4791 Arleriiiscletitsis. 622 Arnhriiiciiie.Se.' Piperacine Arthrography. 481 Arthn'pan. See Choline salicylate Arvlacetic acid derisalises, 758—7611

N-Arylaiohralioic acids. 754—758 Arylonypropanolamines. 542

Acathioprine. 414 actise nietahu.lites of. l35t atttittttttor activity of. 41)5 metabolism of, 12(1 Aeelastine ltydrt.chloride ophthalmic solution. 7)7 Ae.es.tnupic isopropyl alcolnu). 221) Aeimilide. 642 AeJtltrotoscin. 352 Aelocillin. spectrum of actis'ilv '.1. 3(18 Aetoacort. See 'l'riatncinolone acetonide A,,n.'ltlor.iuotd Ste ('hlonua,.odin An. conupoands uttetabuilisutu of. l1)7—Il)8

Areoxifene. 71411. 782 Ascaruasis, 265

prodnigs and. 149—151). 1511

961

Beclovent Sue Beclunoetluasone dipropionate

Becon:tse Sit' Beclomethasone dipr..puu.naie Bee venoms. 835 Belladonna, 574— 575 Beuoidu.ne. 7361

Beoadryl.St',' I)ip)tenltyd.atttiuue Benanomycins. 246 Bet.aeepril hydn.chloride. 646. 6471. 6471 Bendroflnmeth.aeide. 605—611). bOat. hOSt, 6)9 Bentyl. See Dicyclotutine Itydrochl..ride Benealkonuam chlt.rude. 225 Beneanilid. 7611 Bencairocines. 74)1 BettceulrenSe.' Propylltexedritte Ileneetlrine Set' Attipl.eianilne IIeu.cesun.l. 777—778, 7781 Beneeiluonutinu cltluunde. 226

Ascorbic acid. 898—899 Ascorbic acid injection. 899

Ac.. dye.'. sullonantide. 269

Ascorbyl palinuatc. 899

Acolid. 763t Act' linkage. prodnugs and. 149—1511. 1511. 269 Acosemide. 6111

Beneimadole proton puntp inhibitors. 721-726. 7231. 723t. 72Sf

AZT Sue Zidosadine

Benenidaeole. 163 Bencoate esters, as local anesthetics, 677 Beiteocaine. 678. 69)1—693. 691t Beneodiaeepitte anlaginuists. 489 Beneodiaeeptnes. 488—493

Asendun. See Ainuusapiute -Asparaginase. 428-429. 431

Aspirin. 754- 757 as aniithromhouuc. 11$). 822 cardioproleclis-e ellects icC, (14), 822 hypersensitivity to. 8211—821 uutechanisun

of aclioit

atelaholistit 0).

uI.

822

I (8)

Aspro. Sc.' Aspirin Astemui'ole, 712. 7131 Asthma, 813-815 Atacand. See Candesaelan Atenolol. 54-4. 545. 5451 AHterosclerosu'., 622, 657

Ailun.nuhiuu-K.S.-.' Warfarin polassitmi Alivan. Sit' Loraeep.iun Atoisa.statin. 663

unetaholi',tn ii), 7)) Atosaqutone. 262 Atos'aqnone-progaanil. 2911. 292. 2921 Atrttcnnant hasylale. 59)

Atrial natriutdic (actor, mctahuulisnt ol, Ill Atromid-S Set' Cltulibrate Airopine. 574—576.5751 as antispasmodic. 574 as local anesthetic, 676—677 structture—aclisutv relationships lot. 572—573. 579 Alropine analognes. as local aoesthetics.

676-677 Atropine salLite, 576—577

See Auropine sallate Atruusenl .5.'.' Ipntlnupittm bromide Augmentun. See Clasnlanale-aunosicilliut Anreobasidins. 246 Anreolic acid. Si'r Plicamycin Anreontycin hydrochlonde. See Chhntetracycline hydrochloride Antonomic nervous system. .548. 586, 679 Asapro. See Irbesartan Asentyl. See Nortrupts4ine Avenneclins. 267 Avlosnllon.Se,' Dapsoute Asonex. See Interferon Ia Aoopusiul

Axepin Sue ('elepnne Axial cot.li.rtnations. 93), 9321 Asid. See Ni,at.dine Axoletoota. 679 Axon. 679. 6791. 681 Anon hillock, 679 Antuti telondria. 679, 6791 Ae.aclam. Sue Aetreonam disodiunu 5-Azacytldine. 4)18. 41)91

Aealides. 352 Aeapyrimidine nocleosides. 41)8. 41)91

Acaserine. 411

Acatadtne nualeate. III -7)2

Acole antifnngals, 2411—245

Actreonatut disodiuto. .134

B

Bacampicilliti. 3)2—3)3 doable-ester lonut iii, 147, 1481 Bacillus C;dntelte-Gadnn saccine. 2)4 as atitiuteoplaslic. 440, 442 Bacitnuciut. 3(Kli. 356—357 Ilactcrial rcsuoance, 3)11. 3(15 —34)7, 335—336 Baciericitlal lactors. 2)8)— 21)1. 21)11 Bacteriolysis. in i.nnuatue response. 2)15—21)6

Bacieriophage sectors. 165—166. 1661 Ilactrobatu c. Mnpirocun Baker's antifol, 411 HAL.

Diniercaprol

ilulotuutdt,u,,u

u.iii, 26))

Baltimore Clavsuf,cation Scheme. fur viruses, 367. 368t—371ti l3antltine hrt,,oide. Ste Metltantheline brontide

Barbital, 494 Barbiturates. 493 as antlconsnlsants, 504 inzertutediaie-duration. 494. 494t Iong-dnr.ition. 494. 4941 mechanism iii acliu,n of, 493

metabolism of. 76. 77.81.94 109. 493-494 sltort-daratiuin, 4941, 495 s..diiutn salts of. 4t)3 structnre—aclisily relalionships fix. 493—494

stroclare iii, 493- 494 Barium sulfate. 473, 481 Basetsj, 9—17 cuunjugate. t) —

II

delinirion ii), t)

exattiples ut. lIt ionic lorn. u). 15—16, 1Sf. 16i pH ol, calcalalion of. 13 pK. ol, 13—14, 14) strength tiE, 13— 14

Basic tachsun. 227 Basilusimab, 489 Basopltils, (98 l(aycauoa.Se.' Mefnaside

Baycol 5.'.' ('ensastarin Bayer 25(12. St'. Nifnnimox Baypress. See Nitrendipine

Iiaedoxileu.e. 78(1. 782 B cells. 118), 21)2—203

BCCi vaccine, 214 as auttineoplaslic, 441). 442 B('Nki S.'.' ('arrtunsltne 1K' Powder. See Salicylamide Becaplenom. 179 Beclomethasotte dipropionate. 812. 8(4. 8141

Beneimidaeuu)es. 741

ahsorpti.utt tel, 49)1

as anticonsalsants.507—308 cuuutuhinaluurial syntluesis u,f. 46, 461

discovers and developmeuut tel, 489

GABA5 receptors or. 488. 489 us intnuvenons anesthetics. 487 mecluattism tel action tul. 489—49))

ntetabolisin oi. 94, 49(1 protein binding tuE. 49)) struclttre—actis'ily relaiuuunships l.ur, 489—49))

sinuctnre of. 488—489. 489 Bencoic acid. 229. 234 unelaboltsn, ol, (14 Bencoic acid dertvalives. as local ane.sthetics. 690—693. 691u, 6921, 6931

Bencomorphan derivatives. 74)) Betteonatate. 753 Bencuel .rl'pyrene. carcinogetuiciuy ut, 74. 741 Ileneu.yltn.pine. 676—677, 6761 Benephetamine hydrochloride. 513 Bettethiaetde. 605—6)0. 606t. 6(1St. 619 Ben-atropitte otesylate..582 Iteneyl alcohol. 229 metabolism of, 89 Beneyl hencoate. 268 ReneW cltloride. toxicity ol. 118—119 l)eneylpenicillin.31)9—3 II). 309t See isis.. ltenieillin)s) Bepridil hydrochloride. 632 Ileraprost. 825 Beriberi. 886—887 Beiacetylmeuhad.uI. 739t I)eladine. St'. I'uusidone—tunline Bela elimination. pruutein. (73. 1741 Betagan. Sue Levobanolol Betantelhasone, 81)81, 8)l9t. 812

soltthility ,.), 7711t Itetatttelhmts..ne acetate. solnhilily of. 770t Belamethasone NaPO, salt. .soluhility 'uI, 7718 Betapace. Set' Sotalol Beta-particle emission. 456 Belaprodine, 7361, 737 Betaseron Interferon beta-tb Beraxu,ltul. 544, 545. 5451 Belhattechu,l chloride. 511) l(ett.puic See I(elasolu.l Besan.tene. 43)). 432, 874 Bextra. Si'.' Valdecoxih BH acids. 15-16. 161 Biapene.n. 3)8

962

Index

Biaxin. See Clanthromycin Bicalulamide. 431, 1(01—802, 8021 as antincoplastic, 434

with a>.receptor antagonist activity. 546 as antiarrhythmics. 636i. 637 cardioselective, 543—546

Ilicillin. Sic Penicillin 6 beneathine

itonselective. 542—343 fl1-selective. 343—546 structure—activity relationships for. 541—542 Illooth—brain barrier. 5 drug delis cry across, 15%. 1581

BICNT_I. See Carmustine

Bi.Est. See Estriol Biguattides. 226 Bilarcil. Set' Metrift,nutc fliliruhin, metabolism of. I 14—I IS Biltricide. See Binudoprosl. 828 Binning. 58. 61

Blood cells, lineage of. 177. 17sf. 197. 1981 Blood clotting. See Coagulation Blood pressure, regulation of. 642—MS. (>43f—645t

l3ioactivc conformatiott, 931) l3ioclate. Set' Antiheinophilic factor. recombinant Biulnlormatics. 191—19?

Biological activity chcmicul structure and. 17—21, 214,31—41 partition coefficient and. 17—21. 181. 19)

Biological receptor site. 29 Biological response

recotithinant,

194

Biotechnology. 160—194. 858—863 ant't.sense technology in. 193—194

hioitiformatics in. 191-192 cloning in, 164. 166—168 development of. 160. 1611

DNA expression in. l(,7— 68

DNA hybridwttion in. lti6 DNA liga.scs in, 165 DNA microarrays in, 192—193 DNA sequence alteration in. 168—169. 1691 in drug development. 16(1—162.

621.

169— 172

in drug screening. 170—172

enzyme heterogeneity and, 169—70. hOt epitope tagging itt, 69 fundamental techniques of. 163—164 gene expression systems in. 167— 16$ gene therapy in. 194

genetic engineering in, 162—66 genutnic libraries in. 164. 164) genoinics in. 191—193 hybeidouna techniques iii. 187—189. 1881

literature of. 160 tivcrview of. 160 pharntaceutical products lrom, 859t—86(lt. 860—863

pharmacogenomics in, 193 protein processing in. 172 protein synthesis in. 64. 168— 69 protcmtiics in. 193 receptor heterogeneity and, 169—17(1. hIlt recombinant DNA in. 162—166 recombinant proteins in. 164—169. 1691 restriction endimuclea.ses in, 164—loS, 1651. I 65t

subdisciphinc>. of. 161 vectors in. 163—166. 1661 Biohin, 899—9(8)

Biotr.insfonnation. Se,' flr.ag metabolism Bipcridcn Itydroclilonde. 583 Birth control. Sit' Contraceptives Bisguanidines. 672 Bis.N'demethylatcd tt>etabolite ol at-). meihadol. acetylatiimn oF. 122. 1231 Bisoprimlol. 544. 5451

Hithionol. 266 Bum. See Bithionol Bitollerol. 537 Biuret test. 834 Blenonanc. Set' Bleomycin sulfate Bleomycin sulfate. 417—419. 423 Blocadren. See Timulol a-Blockers. 541—546

Blood proteins. 857—858

HMY-25067. 420 Bogus-coin detection, in combinatorial cltcmistrv. 5(1 Boltzntann equation, 931 Bombesin, 835 Bonds. 29—33, 31t, 321, 33f force field calculations for. 923—929 hydrophobic. 831 representation of. See Molecular modeling Bonine. See Meclizine hydrochloride Born'Oppenheiuner theorem, 923 Botaniculs. Ste Herbal medicine.' Bowman's spare, 596, 597 BR. 17 Brudykinin. 856—857 in blood pressure regulation. 644—645. 6441 Brain, drug delivery to. 158, 1581 Breast cancer estrogens for. 779. 782

honnone dependency of. 433-434. 783, 793 progestins for. 787 Brcihitte. Set' Terbutaline Brctyliutti tosylate as .idrenergic agent. 529—530 as amitiarrhythmic. 641

Bretylol Sit' Bretyliunt tosylate Brcs'ibloc, Sit' E,smolol Brevital Sodium. See ..odtumn l3ricanyl Set' Terbntaline Brinionidine. 534 Brinaldix. See Chiipainide British antt-l.ewtsite. See Dimercaprol Broad-spectrum antibiotics. 300 llromelains. 840 Bromobeneette. hepatotomimcmty of. 73—74

Bromtmdipltenltydramine hydrochloride. 702. 703

Isrompheniramine. 71)9 nmetnbolisnt of. 115, 92, 117

Bronsted.Lowry theory.') Brookhaven Protein Database, 39 Itucladin'S. Set' Buchizine hydrochloride Buclizine hydrochloride. 707 Budesonide. 8091, 812. 1114, 8141 Bumetanide, (>10—613.6111.620

Buntex Sit' Ilutnctantde lltmnolol. ttmetaboltsnt of, 1051 Bupivacainc. 678. 690—693. (>92) Iluprenes. See Buprenorphine Buprenorpltine. 741. 1St) Bttpropion. 32(1 Bitrimantide, 7 19—720. 7191 Burnemi. Ste Bumetunide BuSpar. Set' Buspirotte Buspititne, 52(1

Busulian, .Utl lhtttuhart>ital sodmuttm. 494. 494t I)utacaine sulpltattt, 690—1,93. 6911

Butaprost. 824t Butaittltdin. 7631 Butisol Sodium. Si',' Butabarbital sodiiuitm Butoconatulc titrate. 241—242

Buttmrpltaimol turtraie. 7411, 743. 750 .V-t'Butylnimrchlon>cycli-eimtc. tntttabolismtt ol. 86—87

limitylparaben. 229 Butyrylcttolinesier.tsc (IltiChE), SoIl—SOt, SOIl BW245C, 8241

llW,\ 86)tC. 824t C Caerulcmn. 833

Caffeine. 511—512. SlIt Calan. Sit' Ver.tpanmil Calcifedmol. 878

t'alcipotriene. 878—879 Calcitonin. 835 —856 Calcitrimml. 878

Calcium, in vitamin D synthesis. 875—876 Calcium channel blockers. 627—632 as antiarrhytlitnics. 629. liMit. 637

lirs.gcttcr,ition, 629t ttiechanistn .,f action

628—629

sccimttil'gcneratiomt. 6291 types of. (>29—632

as vas,jdilatttrs. 629—632 Calcium>> itmn(sI

in muscle rtmnlruciiitttlrelasatitm. 673—624. 6241. 627—628 properties 1>1. 627—628 as second mtmessengers, 627 -628 Calcitmm ion chanmtels. 628, 6281. (>82. Ste mmli,> ktn cluttmmels

acetylcholine and. 643 Calciuttt pantotlmrnate. 888 Caliclteamicin. 421 cAMP. 531. 353 itt stttsuimh muscle retasation, 623 Campath. Sri' Aletntuzuutiab cAMP rcspommse elenietmt (CRI1l. in drug

screening. 171, 1711 Camptothecin. 426 Cancer breast estrogens for, 779, 782 hormtmonc dependency uI. 433—433, 783. 793

progestins for, 787 cellular abnormalities in. 39(1- 391 cftetnomherapy for. Set' Aimtiueoplastic agents

cnrahility of, 390 in DES daughters. 779 drug resistance in. 392 erudomeirial. estrogens and, 779. 787 lamlure of apitptosis itt, 39) herbal nmcdicines for. 915 inttttuntmtltv'rapy fu,r, 440—442 nmetastasis in. 446—447 prostate jmtmtauudntgen.s for. 81)1—802. 1(021

estrrugeits for. 779 tutnor cell properties it>, 390—394

viral infectious and. 372 Cande'.artamt. (>414-649 Cunnahunoids, as sleep.prumntomiumg agettts, 488

C,nttil Sir

brotitide

Capaatat sulfate. 259 Capecitahimme. 4117,413

as protlnmg, 136—137, lS7f Capillary' electroplmoresis—coupled tuclear magnetic resonance spectroseopy. SI. 61

Capoten. Si'.' Captopnl ('apretimycin, 259 antttubercuhutims activity oh. 254 Cmmpromah peimdetide, 191

Capsaicin, 911>

Inde.v Capsiculn. 910 Captopril. 6.45, 6461

design ol.

94*)

CaralateSi't' Sticritlfate Curbacephems, 327 Carbachol. 559—560, 562

Car Ltna,epine. 506 active nietabolites of. 135i metabolism of. 75, 109 Carhainide pcronide topical solution, 223 Carhamylated alcohobi. 495—496 Carbamyl phosphate. 900 Carbapenerns. 316—31K iutvestigationul. 31K

CarbeniciHin disodium. 309t, 3)3.5cc also Penicillin(s) metabolism of. 09 spectrum of activity of. 307- 31)8 Carbenicillin indanyl sodium. 3091, 313—314 Carbeniuin ions, 395 Carbetapentane citrate, 753 Carbinoxamine inaleate, 702. 703—71)4 Carbocaine. See Mepivacaine Carbohydrates, combinatorial synthesis of. 47. 471

Carbolic acid, 217. 22) corrosiveness of, 14—15 f3.Carbolincs. 4149 Carbonic unhydrass', in renal sodium transport. 59*4. 5981

Carbonic unhydrase inhibitors, 603—605, 6041 preparations of. 6)9 Carbunyl promoieties. 1511—152. 1511 Carboplatin, 428. 43) Carboprost trontetharnine. 795. 7951. 827 Carboxide. 220 y.Carbonyl —glutatitic acid. 883—884 Carbonyhic acid

conjugation iii. 1)7 promoieties of. 144—149. 14Sf— 1491 for prodnigs. 144—149. 14Sf— 1491

Carcinogenicity of atlatovin B. 76—77 of amitIes. 96 of aromatic umines. 93 Cardene. St-c Nicandipine hydrochloride Cardiac arrhytlitnia.s. 634—636

Cardiac eleciropltysiology. 635. 635)' Cardiac glycoside.s. 655—657

Cardiac muscarinic receptors, 551 Cardilate. See Erythrityl tetranitrate. diluted Cardioquin.Sr'e Quinidine polygalacturonate ('ardioselective 543—546 Cardiovascular agents, 622—674 antianginals. 622—627 untiarrhytltmics, 634—642 anticoagulant'.. 663—668 aniihypertrnsive.s. 642—657 anlihipittemics. 657—662 antiihyroid agents. 673—674 thyroid hormones, 673 s'asodilutors, 622—634 Cardiovascular disease, 622—623. (sZ3f Cardizem. St'e Diltia.retn Cardura. See

Carisoprodid. 496 Carmiituniycin. 415 Carmustine. 399. 41)1

decomposition of. 395. 3i)hf Caromec Sm' lvcrmcctin a.Carotctie. 869—870 a-Carotene, 869—870. Sec ti/si, Vitamin A excess of. 87) fond sources of, 869—Kill

product. 1475

iii vitatititi A synthesis, 869—870 gamma.Carotcne. 869—Kit) Carotenoids. 869—870. Sec also Vitamin A absorption of, 870 land sources of, 869 structure—activity relationships for. 869—87)) in sitammn A synthesis. 869—870 Carteolol. 543. 5441 Cartrol, See Cunleotol Carvedilol. 546. 5461 Casodes See Bicalutamidc Catatlam. Sec I)iclofenac potassium Cataleptic aiiesttiesia. 488 Catalysis, en'eymatic. 835—837. 8361. 8371

('atapren. See Clonidine hydrochloride Culecholamines. 524—547. Sec also Adreuergic neurs,transmitters adrenergic receptors and. 527—528 biosynthesis of. 524—525. 5241

drugs affecting, 52)) propenies of. 524 receptor', for. 527—528 storage and release of, drugs affecting. 529 structure 01'. 524

as sympathomimetics, 532 uptake and metabolism of. 525—527, 526f Catechol.O.niethykransl'eruse (COMT). 125—126. 526—527. 5261

Catechols. methylation of. 125—126 Cationic dyes. 227—228 Cationie surfactants. 224—227 Cavcrject. See Alprostadil

CC-l065, 420, 42))' CCNIJ. See Lomustine eDNA. in combinatorial chemistry, 49 eDNA libraries. 164. 164t CEA-Scau. Se'i' Arcituinomab Cehione. See Ascorbic acid Ceclor. See Cefaclor Cedax. Set' Ceftibuten CeeNtJ. See Lottsustiiie Cefaclor, 32(8, 326—327, 326t Cefadrosil. 3201. 326, 326t Cefadyl. See Cefamandole nafate, 32 It. 3261. 328 Cefarolin, 3211. 324. 327—328. 327* Cefepime. 333 Ceftxime. 320t. 326t, 33) Cefn,eta,ole sodium, 322*. 326t. 330 Cefobid. Sec Cefoperuzone sodium

Cefonicid sodium. 3211, 326*328 Cefopenienne sodium. 3211. 324. 325. 3261, 329 Ceforanide. 3211. 3261, 328—329

Ceiolan. Ste Cefotetan disodium Celotaxitne sodium. 321t. 3261, 331 Celotetan disodium, 322*, 3261, 329—331)

Cefoxitin. 324 Celositin sodiutti. 3224. 3261. 329 Cefplruiite. 332—333 ('el'podoximc pronetil. 320*. 323, 326*. 3311—331

doable-ester form of. 147, t48l' hydrolysis of. 147. t47f Cefprozil. 320*. 326*. 327 Cefrom. See Ccl'pirume Celtazidime sodium. 321t. 326*. 332 Cef)ihuten. 332 Ceftin. See Celtinixime axetil CeUiioxitttc sodium. 32 It. 326*, 331 Ceftriasotie disoditint, 320, 3261. 331—332 Cct'uroxime axetil. 32 It. 323.3261. 330 double.ester latin of, t47. 1481 Cefuroxitne sodium. 32 II. 326*. 330

963

Cefail. See Cefprozil Celebres, See Celecoxib Cclcconib. 76*). 822—823 metabolism of. 77 Celexa. See Citaloprain Cell cycle, 391. 3911 Cell death, programmed. 39(1—391

Celt.medlated imniunity. 202—203 Cell membrane. See Membrane(s) Cellular antigens, in exceinc praductiun. 207 Cellular immunity. 20*) Cellular retinol-hinding protein (CRBP), 869 Celontirt, See Methsuximide Cenestin. See' Estrogen(s) Central dogma. 162

Central nervous system. 548. 679 Central nervous system dcpressant.s. 485—508 unticonvulsants/antiepileptics. 485. 503—508 atitipsychotics, 485. 496—503

anxiotytics, sedatives and hypnotics. 485—4% general anesthetics. 4115—48)4

overview of. 485 Central nervous system stimulants. S10—S22 $'amylamino hallucinogens. 520—521 antidepressants. 514—520 central synipathominietics. 510. 512—514. 5121

dissociative agents. 522 mcthylxnnthincs, 511—512 Central sympathomimetic agents. 510. 512—514. 5121 Cephadrine. 320*. 325 —326. 326t Cepbalexin. 320*. 325. 3261

Cephaloridinc. 324 Cephalosporic acids. 322 Cephalosporitts. 318—334 acid resistance ti), 326* adverse reacttons to, 325 antipsendomonal. 325, 326t

catechol.containing. 333 classification of, 325 degradation of. 3)9—322. 3231 discovery and development of. 319 drug interactions with. 325 first-generation. 325. 3261 fourth.generation, 325, 3264 future des'elopntcnts for. 333—334 historical perspective on. 3 18—319 fl.lactama.se resistance of. 323—325. 3241 /3'lactrun of. 322 mechanism of action of, 31)05 MTT.group, adverse reactions to. 325 nomenclature for. 3)9 oral. 3201. 322—323. 326* parenteral. 320t—322t. 323, 326t

prodrug forms of, 147, l48f protein binding of. 3261 research directions for, 333—334 second'gener.tiion. 325, 3261 sentisynthetic, 3)9 spectrum of activity of. 323. 3261 structure—activity relationships for. 319 structure of, 3201—3224

third.generation. 325. 326t types of. 325—334

Cephalothin, 320*, 324, 326), 327, 328 Cephamycins, 329. 330 Cephapirin sodium, 3201. 326*. 328 Cephradine. 323 Ceramic beads, in citmbinatorial chemistry. 49. 60

Cerezyme. See Imiglucerase Cerivastatin. 663 Cerubidine. See Daunorubicin

964 Cerva'etn Set' Genteprost Cervidil. Set' Prostaglandin Cestocide. See Niclosamidc Cestode infcstations, 264—265 Cetirt,ine, 714

Cetylpyridinitim chlonde. 226 Ccvitamic Acid. Scr Ascorbic acid cGMP. in smooth muscle relaxation, 2641. 623—624

Chagas' disease. 260 Chamomile, 911

CItation's steric parameter Vt). 21 Chelalmg agents. 463 Chemical bonds, 29—il. ut. 331, 341 force field calculations for. 923—929 Chemical contraceptives. See Contraceptives Chemical databases, searching methods for. 39—40. 55—56. 930-933 Chemical diversity definition of, 61 quantification of. 56—58 Chemical libraries, 43 generic. 43. 441 mixture, 43. 441 Chemical structures databases of. St't' Chemical databases drug—receptor interactions and. 31—41

models of. Se.' Molecular modeling physiologic activity and. 17—21. 28. 31-41. Set.' also Drug—receptor interactions Chemotactic factors. 200 Chemotherapy prodrugs in. 156—159 site-specific delivery of. 158—159 Clttckenpoz vaccine. 211. 2l2t Chili pepper. 910 Chitneric antibodies. 189 Chimeric proteins. 168—169 in drag screening, 172 Chinosol. Set' 8-Ilydroxyquinolinc CItloral hydrate. 496 active mctaholites of. 135t metabolism of. 103 Clilorambucil. 4181-401 Chloraminophcnamide. 6041 Chlornminophenc. 400—401 Chlort,mphenicol. 3001. 360—361 metabolism of, 101—103, 107. 112—114 as prtxlrug. 4—5. 142, 1431

solubility of. 4 taste stf. 4

Chloramphcnicol palmitate. 361 as prodrug. 4—5

soluhilily of. 4 Clilorampttcnicol sodium succinatc. 361 Chlorvyclizine hydrochloride. 706. 707 ('hlordiazcpostde hydrochloride. 489. 490 Chlorhexidine gluconate. 226—227 Chlorinated pesticides, drug metabolism and. 131

Chlorine-containing germicides. 223 —224

Cl,lorua,odin. 224 Cltlorobutanol. 229 Chtorucresol, 222 Chlorodiphenhydraminc. 702 Chlorolomt, metabolistu of. 101 p.Chloro-m-nylenol 221 Chloromycetin. Set' Chlorstmphcnicol p-Chlorophenol. 221 Chloroprucaine hydrochlortde. 690—693. 691t Chloroquine. 287—288. 287$. 295* Cltlorolltiaiide. 605—61(1, (tOôt. 608t. 619 Clilorphenesin carbatnate. 495—496

Chlorpheitiramine. 7014 ntetubolism of, 1(13, 114

Chlorphc,ttcrmine. melabolism of. 92 Chlorpromazinc. 498-499. 499* active metabolites of, l3St metuhol,sm of, 71. 85, 87 Chlorpropamide, 668. 669 nietabolism of, 81.')4 Chlorictracycline hydrochloride, 345*. 346 Chlorthalidone, 269. 607—610, 6071, 6091, 6l9t Cl,lor-Trittteton. See Chlorphenirantine Cholangiograplty. 479—480 Cholectilciferol. 875, 877 preparations oF. 878 Citolecystography. 479—48()

Cholecystokinin'panereozymin (CCK-PZ). 854—855

Cholera vaccine, 212*. 214—215 Cholesterol elevated levels of. See Hyperlipoproteinemia

in lipid tnenihrane. 231. 2321 soluhility of, 770* steroid synthesis from. 768—770. 7(191 Citolestyramine resin. 660—661 Choline. 901 Choline acetyliransferase (ChAT). 553—554. 55Sf. 5541

Cholinergic blocking agents. 548. 572—586 ttnttnoalcohol esters, 579—582 antinoalcohol ethers, 582—583 auninoalcohols. 583—584 amittoantides. 584—585 atttisccretory effects of. 573—574 antispasmodic effects of. 573—574 drug produco. 575—586

indications for. 574 miscellaiieous. 585-586 mydriatic effects of. 573—574 solanstceoas alkaloid.s and analogues. 574—579

structure—activily relationships for. 572—573. 579

structure of, 575 synthetic. 579—582 therapeutic actions of. 573—574

Cholinergic drugs. cholinergic blocking agents. 548. 572—586 cltolinergic receptor antagonists. 558—572 ganglionic hlockittg agenls. 586—589 neuromuscular blockittg agents. 589—595 stereochentistry of, 555—556. 55Sf. 555t, 5561. 551st

Cholinergic nerves. 548 Cholinergic neurochemistry. 553—554 Cholinergic receptor antagonists. 558—572. 559,.

cltolinestcrase inhibitors, 560—569

irreversible, 567-569 reversible. 560—567 Cholinergic receptors. 548—553

acetylcholine th/:ra,is conformation and. 34—35, 341

activation of. 552. 5521 muscarinic. 550—553. 551f, 5521 nicotinic, 548—550, 5491. 5491 Cholinergic stereochemistry. 555—556. 5551. 555t. 556f. 5561

Choline salicylate. 755 Cholinesterase inhibitors. 563—569, 563t Cholinestera.ses. 560—563

phosphorylation of. 568. 561lf reactivation of. 5681, 569 Cholinolytic agents. See Cholittergic blocking agents

Choloxin. See Dextrothyroxine sodiutn

Choritmic growth-hormone prolactin, ((45 Christmas factor, recombinant, 185 Chromatography affinity. tn receptor isolatioti. 28 itt cotnbinatorial cltemistty. SI higlt-peth,rmance liquid. 51. 833 ion exchange. 834 paper. 834

supereritical Iluid. SI Chromic phosphate P 32. 444—445

Cltnimomyctn. 417 Chromosome walking. 167 Chrysin. 784. 7l14f Chyloinicrons, 657—658. 869 Chymar. See Chymottypsin Chymottypsin. 838. 839* Cibalith'S. S.'t' Lithium citrate Cicaprosl. 824* Ciclopirox olantinc. 234—235 Cidex. See Glutaraldehyde Cudotovir, 378—379

Cigarette smoking. drug metabolism and. lii Cilastin-intipeneni, 317—318 Cimetidine, 71'). 7191, 72(1—121, 720*. 721t

nietabolism of, 99, 101 Cinchocuine, 678, 690—693, 692t Cinchona alkaloids, 286—287. 2861

Cinchotiisnt. 286 Cinobac. See Cinoxacin Cinoxacin. 248-250 Ciprolloxacin. 248, 248r, 249—254) cit isotners, 31—32 of acetylcholine. 34—35, 341 Cisplattn. 4311—431

Cispro. See Insulin injectt.m Citalopram, 519 Citmvoruo, factor, 41t) Cladribtne, 405, 412 C'laforan. See Cefotaxinie sodiutti Claritltromycin, 351—352 Classification tecltnicjues. 24—26 Clavulanate-antoxicillin. 316 Clavulanate potassium. 316 Clavulattatc-ticurcillin. 316 Clavulanic acid. 315. 3151, 316 Clays. as contrast agents. 477 Cleavage reactions, in combinatorial chemist,). 49,61 Clema.stine lumaraic. 702, 704 Cleocmn. Set' Clindamycin hydrocltloride Cleocin Pediatric. .S't',' Cltndamycin palmitate hydrochloride Cleocin l'hosphate. Sc.' Clindatnycttt phosphate Clidiniuni bromide. 579—58(1 Clindamycin hydrochloride, 354 Clindamycin palmitate hydrochloride. 355 Cttndaunycin phosphate. 355 as prodnig. 149. 1501 Clinical trials, of atttineoplustic agents, 394 Clinoril. St-c Sulindac Cltoquinol. 234 Clistin. Set' Carbinoxamine tnalente Clobenprobit, 728—729. 729f Clobeta.sol propionate. %08f. 81$)t. 812

Clocorlolone pivalate. 8081, 812 ('loderm .5,'.' Clocortolonc pivalttte Clolazimine. 257 Clofibrate. 659 active metaholites of, 135* metabolism of, $09 Cknnid. See Clomiphene citrale Clontiphene citrate, 781. 781 f. 782. 783 Clomipramine hydrochloride. 517 Clonaiepam. 5(18 metabolism of, 107

!ttdr'.t

Clontdtue hydrochlonde.533—534. 653 metabolism ol, 70

('Inning, 164. 166-68. 861). Ste a/it; Biolechnitlogy: Recotnhinanl l)NA technology applications 01, 167—168

cI)NA libraries in. 164. 164t DNA ligases in. 164—165 Innetional expression. 166—167, l67t genoniic libraries in, 164, 164t homology-based. 167, 1671 host cells in. 166 methods of, 164, 1641 positional. 167, 167i promoters in. 168 receplor. 28 eeslrcton endsittucleases in. 164—165 slept in. 858—861) vLctOIs in. 165—166.

Comhidex. See Ferutttoxtr.ut Cttmbinatorial chemistry. 26—27. 43—h3 analytical techniques in. 5 1—52 detection in. 50 carbohydrates in, 47. 47f chromatography in. SI eleitsage reactions in. 49. 61 tkconvoluuion in. 26. 271. 61 development ol. 43 tttolecules in. 46—48. 461. 471 effectiveness of, 58—60 litur-cttmponent tJgi reactittn in. 49. SOf goal of, 43

hotnology tnodrling in. 56 infrared spectroscopy in. SI iterative deconvolution in. 50 lead structures in. 59—60, 591,61-62 libraries in. 26—27

661. 168

('lopamide. 607—610. 607f. 609). 619 Clopitlogrel. 633 Clttproslenol sodium. 828—829 Clttraeepate diptstassiuto as unticonvulsunl. 5118 as anniolytic. 491 Clorexolone. 607—610. 6071. 609), 619 Cloepactin. Set- Osychlorosene sodium Clotrtmazole. 2411—241

Clotting. Ste Coagnlation Clonacillin sodinin. 3091, 311 ('Ioeapine. 500. 502 Cloearil. See Clocapine Cluster analysis, 58. 61 CNDO method. 937—938 Coagulation. 664—667. 857 ntechanisms of. 663, 664), 883 platelets in. 665—667 prostaglandins in. 666—667

vitamin K in. 883 Coagulation factors. 664. 6641. 664) recotnhinant, 167—168, 183—185. 665 Coal tar analgesics, 760, 761t Cobalamin concentrate. 896 Cobalamins. 894—896 deficiettey of. 895 (olic arid tttetabolism antI, 896—897 products. 895—896 properties iii. 894—895 toxicity oF. 895 Cobra venom sttlation, 835 Cocaine, as drag of abuse. 520. 522 as local anesthetic, 676, 677, 6771. 678. 690 metabolism of. 109 Codeine. 732—733. 733). 738. 745 metabolism of, 87, 126. 129 Codeine phosphate. 745 Codeine sulFate. 745 Codone. See H)dtocodotte hilartrale Coen,vme I, 888—889. 8891 Coenryme II. 888—889, 8891 Cognex. See Tacrine Itydtstclttoride Coherin. 845—846 Colcemid. See Demecolcine Colchicine. 424, 426 Colesevelam. 661 Colestid. See Colestipol hydrochloride Colestipol hydrochloride. 661 Colisuimethale sodittm. 359 Colislin sulfate. 359 Colon, drug delivery ttt, 158 Colony-stintulaling (actors. reconthinant. 178—179.863 Color tests, for proteins. 834

Coly-Mycin M.See Colislitnethale sodium Coly-Mycin S. Set' Cttlistin sullitte

965

agents lbr. 478, 479f. See u/stt Cttntrast agenls

system Itir. 454—455. 4561 Computer-assisted drag design, 27—41,

91t)_tJ45 Sec 0/tn Mttlecular modeling ab initio methods in. 938 actise an;tlttgae approach in. 944 advantages ttl, 9211—921.926

computatit'nal chenttstty in. 922—923 cttmputer gr.tpltics itt. 9211—922. 921—922. 9211. 9221

cotfformatittnal searching itt, 9311—933 depth cnetng in. 921 developnteut tif. 9211—921 drag—drag interactittns and. 944_t)45 dntg—fttod interactittas attd. 944..t)45

ettergy minintization ttt. 929—930, 934 esantples ttf. 939—944

delittitittn ol, 62

force field ntethtttjs itt, 923- 929. Ste 0/vt,

design of. 55—58

Fttrce field methods geometry ttptitnii.atiott itt. 929—9311 in lead discovery and deselttpntent. 9211 ntolecular dynamics sintulatittits in. 933- 935 ntttlecular models in, 9211—922. 9211, 9221.

exploratory. 56 focused. 56.61 generic. 43. 44f ltigh-throaghput screening of. 26—27, 4)1. 41)1, 43, 53—54. 541. 55. 944

ntisture. 43, 441 optimization. 56 lugging ntetltods for. 52—53. 521. 52t virtual un silicttl screening ttC 54—55.56. 919 linear chain molecules in. 45—46

linkem in. 48-49. 481, 62 Lipiaski Rule of Five in. 41). 55 mass spectrometry in. 51—52 media in. 43. 451 Merrifteld synthesis in, 43. 441. 481

microwave Iteating in. 47 ttaturul prodacts in. 47—48. 471 nuclear magnetic resonance spectroseopy in. SI

one-bead oae.conqxtund synthesis in,

46-48. 50, 62 ortbogttnal pooling in, 5(1—SI, 62 overview (tI. 43 peptides in. 43. 441. 451 peptoids in. 43—46, 451, 63 polynterase chain reactittu in. 52. 62 polymer beads in. 48—49. 60 pttoling strategies in. 50—51. 53.62 positional scanning in. 51. 62—63 solid-phase. 46—49. 461 solid supports in. 49, 63 tagging of. 52—53. 52f. 52t soluble supports in. 49, 63

lagging ttl. 53.61 solution-phase. 49. S(tf split-and-mix synthesis in. 43. 441 subtractive deconvolation in. 50 terminology of. 60—63 trends in. 60

yield of reactiotts in, 47 Comhi-l'atch. See Hormone replacement therapy

Comfort algorithm. 933 Cttmparine. See Prochlorperucine maleate Cttmplementarity-determining regions (CDRs), 188

Completttentary DNA. in ctttnhittatorial chemistry. 49 Cttmplement pathway altematise, 201. 2021 clas.sicul. 203. 2031 Computational cltentistry. 922—945. Set' tt/stt Computer-assisted drag design Computed tomography. 454—455. 478. 4791

See a/to Molecular tttttdeliug oserview ttf, 919—9211

pltanttacopltttre cottcepl in. 934

predictive Al)ME in, 944-945 quantum mechanics methods in. 923.

935-939 screenitig tn Ste Screemting semtrntpirtcal ntethods in. 937—938 55. 939—93-I

3D imaging in, 921 visualiz.atitttt techniques in, 921 Cttntputer graphics. 921—922, 921t, 9221. Set' ti/so Coatptttcr-as.sisted drag design COMT 125-126. 526—527 Ctttttvax. 186—187 Cones. 871, 872

(ttnflguralitttt interaction methods. 939 Cttnformational databases. 39—40

Conlortnalit'nal tle.sihtlity.34—35. 34). 9311—931

Ctmnlitrtnatittnttl tsomers.32—33 Confonnatittnal searching. 930—933

Cttaforatatittttls) axial, 93). 932t htttactive. 9311

definition of. 9311 equatorial. 931. 932 Con/ttettter. 931)

Cottlitet algttrithm. 933 Congenttn. See Benetropine mesylale Cttttjugate acid—conjugate base pairing. 101—121. II

Conjugate gradient approach. 931) Cttnjttgation reacttttas. 8 in drag metabolism. 65—66. 65t, Ill —126 Connectivity tables. 23—24. 24t Connolly surface. 922 Contntceplives. 789—795 depressittn antI. 893 development ol. 789—791) estrogen itt, 779 ttvulatioa tnltibitstrs. 790—794 hiphauic combinations. 791). 791t—792m

classes of. 790. 79lt develmtptitent ttf. 790 enmeegency, 793t

inmplants. 792t. 7931, 794 injectable depot. 792t. 793—794

IUD. 792t, 794 ttttttmopltasic cotnbintttit,ns. 79(1. 7911

966

ku/tx

Cotitraceptises (iottritttted) prixlttcLs. 791t—793t. 793—794

progestin-oitly. 792t. 793 safety of. 790-793 lr.tnsdennal, 792t. 794 trtpha.sic combittaliouts, 790. 7921 poslcoital. 794—195

pritgestins tn 787 relative effectiveness ol, 795, 7951 tryptopltnn titetabiilisnt and. 893 Contrast agents. 472—484. See alto Radiopharntaceatieals adverse reacttons to, 481 (or arteriography. 478. 4791 for arthrogeaplty. 481 for clntlangtogrnplty, 479 (or cholecystography. 479 for cotnpnted ttnoitgmphy. 478—479. 4791 definition of', 473 for excretory arograplty, 478 gadolinitint. 476 for gastrotntesiinal stndies. 48(1—48 I. 4801 high-osntolar. 473. 474t (hr hysterosalpingograplty. 480. 4801 mdtcaliott.'. 11w, 4741

ingestible, 473 (hr intr.tvenous pyelography. 478. 478f for intravenons nrogtaplty. 478 ionic ratio 1.5. 473. 474t iron oxide. 476 low osniolar, 473 for rnyelography. 481) ostnolality of. 473—474 parantagnetic. 475—477, 4761. 4831, 484 products, 481—484 types of'. 474t altensonnd. 477 viscosity of. 474 water.insolnble, 475 473—475

Ctaixidation. 822 Cophene-X. See Carbetapentane citrate Cordarone. See Atni'tdarone

Coteg. Sit' Canedilnl Corgard. See Nadolol Coronary atherosclerosis. 622 Corticorelin. 843 Conicosteroids. endogenoas. 81)3—815. See

a/au Gincocorticoid(s); Mineralti corticoidis); Steroidl vi Cortientropin. Ste Atlrenoeorticotropie ftnrtnnne tAC'rIl) Corticoropiit gel. Sit Repository corticotrtipin injection Corticotropin injection. 842. 842t Corticotropin—releasing hormone. 841 Corticotropin tine, See Stenle coritcotropin ztnc hydroxide snspension Corlisone. 81171, 80'h, 811

active tnetabolites id, 135t as attttneoplastic, 435

biological a'tivities of. 8116 biosynthesis of. 8114—805. 8041

metabolism of, 805. 8051

relative activity of. 809t. Conrosyn. See Cosytttroptn Corvert. See Ibutilide ('orynanlhtne, 541 Cosinegcn. See Dacttnontycin Cosyntrrtpin. 842t. 843 Cotazyrn.Sei' Pancreltpase Cotinine. metabolism of. 95 Cough snpressants. 752—753

Coalomb's law. 927. 9271 Conntadin. Ste Warfaritt sodinro

('outttcstrol, 778- 779. 778f Cosalcttt bonds, 29—il, 3lt COX-l, 8(9, 8191, 822 CON- I inhibitors. 754 COX-2. 819, 8(91. 822 COX-2 itthibitors. 754. 822-823 Coiarr. See l.osartatt CPK models, 9211. 921 922 Cranberry, 912 Cresol. 222 Crittcal titicelle eintcentration, 224 Crixivan. See lttdiit;tvir ('rontolyn stnlinnt. 715-716 ('rittantiton, 268 Crucx. Sit' Undecylettic acid

Cyproheptadine. ill metabtulisttt of. 76, 87. 114 Cystic fibrosis. 185. 194 Cystic fibrosis gene. cloning of, 169 Cytadren. St-c Atnittogluteultinuide Cytarahtne. 41(7. 413 Cytochronte P-450 encyittes drug—drug interactitutts attd. 13(8. 131

in intestinal tttacosa, 66 sot> ntes of. 67. 67t. 1318. 131 vs. nttttuoanuine oxtdases. 9)

nontenclatnre for. 67t oletintc destruction iii, 77 in oxidative reactutuns, Wi—69, 681. 691, t)l

getwtic differences in. (29 sex differences in. 129 - 130 in prodrug activatiott, 152

Cryptosporidiosis. 2611

('rystalline cmc insnlin. 851. 851t. 852' Crystallttria. salfanilamide-related. 274 Crystal violet. 227 Crysticillin. Set' Petticillin G procaine Crystodigin. See l)igitalis Cnetttid. See Cltolestyranttne resiut Curare. 590

Cashing's syndrottte. sIt) Ctitatteons tnycoses. 231, 2311 titpical agenLs far. 233—235 Ctttivale. See Fluticasonc propionate Cyanocobalatnin. 894—896 deficiency of'. 895

lithe acid ntet:tbolism and, 896-897 prodttcts. 895—896

in steroid buasyttthesis. 768—7711 tissue distrthtttitutu 1)1. 66, 67. 91

Cytokities futtctiiuns 1. 177. 177t itt ltrtttattupoiesis. 177. 1781 reconthinttnt. 177-179, 1771. 861 -862 ('ytontel. Set' Liothyrtittine srntittnt Cytosar'U. Set' ('ytnsine arahinuiside Cyltusitte ar.tbinnside, 4117. 413

Cytotec See Misoprostol Cytotoxic agettts, for cancer. Sit' Antineopla.stic agents Cyuits cite Set' (itnciclsivtr ('ytoxan. Sit' Cycltipltospltautiide

properties uI. 894 -895

toxicity of. 895 Cyattocobalatttitt rttdtoactive cobalt capsnles. 89(u

Cyanociuhalaittin radioactive cobalt solntiott. 896 Cyclactucine. 741). 751

Cyclrtu. Ste Norgestimate

('yclic AMP. 551, 553 itt sntaotlt muscle relaxation. 623, 6241 ('yclic AMP re.spottse eletnettt ICItE. tn drug screening. 171, 1711 Cyclic gttantistne monophosphate tGMPt. itt snnuoth muscle relitxatiott. 2641. 623 --624

D

t)4I'. See Stavtatitte I)acarba,iite, 402 actis atiunt nI. 398. 3981

Dacli,utnab, 189 Dactinomycin. 4(4. 415. 421 I)aidzein. 778—779, 7781 Dalfoptistitt-qairtnprustun. 363 Datgatt Sue l)e,oeine I)alntane. Ste Flnrai'epant I)anaiol, 7991 801 Dautttcrine See Danaittl I);tntnilette. metabolism of. (07 l)apsone. 28)1

Cyclicine hydrochloride. 7116—71)7 Cyclicitte Lactate Injection, 7117 Cyclit'ittes. 7(16—7(17. 7(161

('yclocon. See Antcinttnide Cyeltucytidine. 41)7—41)8

Cyelognanil-atiuvaqnone. 29)f. 292. 2921 Cyelogyl. See Cyelopetonlate hydrochlortde Cyclohexanol, eonfonnations of. 931—932. 932t

antttabercttlar activity iii. 254 tttetabolisttt at, 1)3 l)aranide. Sue I)ic(tlorpftenatnide l)arbid. See Istupropantude iodide Daricon. Sit' Oxypltettcyclimine hydrncltlnui Dark adaptation. Sift I)arvon. Set' Propoxyphene hydrochltmde See Propoxypltette ttapsyfate Databases

Cycltultexintide. 337 Cyclonteiltycaine sulfate. 69(1—693, 691t ('ycltnixygenase, istulorms tuf. 169 Cycliutuxygena.se-l. 8(9, 8191, 822 Cycltiuuxygenase- I inhibitors. 754 Cyelooxygettase-2, 819—821), 8191. 822 Cyclrnuxvgenase-2 inhibitors, 754. 822-823 Cyclooxygenase pathway. 818. 8191 ('yclopar. See Tetracycline Cyclopenutulate hydrocltlttride, 58(1 4(8)

activation iii, 395.3L36, 3961 metabolism of, 95—96 Cyclorphan. 740 Cyclutserine. 259. 3l81t

antituhercnlar activity of. 254 Cycltitltiaeide. 6(15—611). 6961. 6()8t. 62(1

Cylert.Si'e Pemoline Cylic AMP, 553 CYP isticynues. predictive ntodel for. 945

biological. 58 cltetnical stntcture, 511 muning of. 58 searching tiE. 39—40, 55—56 confornmtiona). 9311—933 itt library ulesign. Sb 31) sunictaral protein. 939. 9391

Data tttiitittg. 58 Data warehnttse. 58 I)annrtmycin. Sit' Daanoruhicitt Itydrochltn l)annontycinol. 4(6 Dauttturnbicin hydrochlutrude. 4(5. 416, 422 ntetahtilisnu tif',

11151

l)axolin. Sit' I.oxapine suecinate I)aypro. Ste Oxalirtvrin dCF. See Peittuistatttt ddC. Set' Zatlcitithitte

ddl. See l)idanosine DDT. for tniusqaito control. 283 Deantidatituit. pruitetn, t 73. 1741

I)eaiapyriittidine nucirosides. 408, 4(191 Dehri'ax(ititt. tnetabolistn ol, 771 Dc Brogue relationship. 936 I)ecal)arabolin. See Nandrolone decanoate lkcapryn succinati, cc Dosylaittine saccinate l)ccloinycin. Set, 1)enieclocvcline

))estrontetborphan hydrtibrotnide. 753 Destrontoramide, 7)8, 739t I)estrtttltsriesine sodium. 66)t I)e,ocine. 75))

Dihydrocodeinone. 733. 733t Dihydrololate ttductase inhibitors, 279

1)l4PG, 377—378

I>ecOfltatflinahifln, 2181

Dia)tetes netlitas. 85)1—85) l)iabittese. See C)tlttrjtropamide

l)ihydrotnorphtne. 733. 7)3t Dibydrotttorphinone. 733. 733t Dihadroittorphone, 745--746 I)ihydropyridine. as drag delivery system.

l)eeonvoluium, 26. 271. 61 iterative, 5)) snhtractive. 50

DiaBeta. See (ilyhunde

Demades. See Tor.scni,de

l)tacetolol. 545. 5461 1)iacetyltttorphine. 731. 73). 733t, 745 Dialen. See Dipheny Ipynilitte ltydroe)tloride Dtagttostic itttaging agent'. See Raditipltatmacenticals l)iantagnetic sabstances, 476 Diattucron. See Gliclande Diamos. See Acetazolamide l)iatnpromide. 741 l)ianabol. See Metltandrostenolotte l)iaparene. See hlethylben,ethontaitt chloride Diapid See Lypressin

Detnecariutti brotitide. 566 I)erttcvlocycline. 345t. 347 I)emecolcine. 426

l)iastase, 841) l)iasten.,onters, 35 l)iatrieoa)e. 481—482

l)cmcn'l Set' Sleperidine

Diaiepam. 49(1-491 active tnetabolites ol, 134—13S. I 35t as anesthetic. 487

Delensins. 21)1

Dehytlratcd ethanol. 221)

acid. stilubility of.

77111

I)ehydrocmettne. 261—262

1)1II:A)

biological a'livity til, 797, 7')KI biosynthesis '8. 7691. 771). 797 nieiabOli5ttt ti). 797

Delavitiline. 383

t)cntovepani. 49(1 l)cniser. See Metyrosine

l)enataration. proleict. 173- 175 Denatured alcoltol, 219 Dendrimers, in combinatorial cbetnistrv. 49. I, I Dendrites. 679. 6791 Denileakin diltitos, 183. 442 Dc nato drag design. 55 lanctional theon'. 93') Denvir. Ste Penetciover I)eosscoiornt)ctn. 41)8 I)eosycortisone. 81)6. 81)71. 8)8)1

vs auttteonvnlsattt, 508 as anvitely tic. 49(1—4') I

otetaholism at. 71. 94, 11)1. 133 l)iazeqntttte. 395 INazoside. 654—655 l)tbeneocsclttlteptattes. 711—712. 7121 Diheniireyeloheptenes. 711—712,7121 Dibeniy)inc. See Pltenovyben',antine l)throtttt,matmitol, 395 l)ihucatne Itydisechloride, 678. 690—693. 6921

l)eoivnboauclcase I. recombinant. 185- 186 6-I)ensvteiracyclines. 342. 344 -345 Depade. Ste Naltrestine I)epakeae. Ste Valproic acid I)ependence liability. 732 l)qtoianeatiott. 68)). 682 Depo-I'tment. 792t. 79)

1)11'. See I)acarh,iaine

Depressants. Set' Central aces ints system

l)ieloxaeilitn smlitint, 309t, 311 See otatt Pctttcil)itftsi 1)ecodttl. See Hydrocodt'tte bitatirate Dicamarol, 667 Dicycloinine hydrochlortde. 5811

depressants

Depth ctieittg. 92) l)emtattip)tytoses. 23). 23 It topical agents for. 233—235 l)tiS daaghters. 779 I)esencs See t'ndecylenic acid lkserptdnte. 529 l)e.stltirane. 486 l)esiprannne bydtochloride. 5)7 lksuno(tressitt acetate )Dl)AVP), 8461. 847 l)esogen. Ste l)esitgestre( Destigestrel. 7871. 789

in contraceptives. 791t. 792, Desottide, 8081. 812

Sit' Dcsot,ide l)esoxitttetasotte, 8(18). 8)2 Desosya. See Methantphetatnene I)esyrel See Traetnlotte

l)etovil'ication, delinition ''I. 65 l)etrottmramide, 73')) 1.2-Deuteride shin. 71. 721 Devatttetltasone, 8))')t. 812 Deshrontphenirantine ttt;deate, 709 Desc)tlorphentratttine ttialeate. 7)18— 709

Desedrtne. Ste l)estroatuphetattune Deslenllarantine.5 14 l)espanthenol, 888 1)enraiosaite, 445, 446 Devtroatttpltetamtne. 512. 513 Deatrornetlnuphan. 739 tttetaholistn ol. 86

N.N-Dichlorodicarbonamtdine. 224 Dicltltirteisoproterenoi I l)CI 1. 541 —542 acid. 224 l)ichtlorphettatnide, 6(41. 62))

Dicloliniic potassium, 759 Dielvifenac scaliunt. 759

I)id.itti'sine, 3811

I )idtvv See Benep(tetatttitte ltydrticltloride l)ienestoii, 777—778. 7781, 781

Diet. drug ttietabiilisnt anti, l3lt. 1)2. 944—945 I)ietltylcarbama,epitte citrate. 265 Diethy lenediantine. 265

Dtcthylpropion. SI) ntetaholisttt of, 1051 Dtethylsttlbestrol as aittitieoplastic, 434 cancer ut offspring and. 771) metabolism iii. 77 preparations of. 780 as siittiiaeity probe. 56. 57t stnictitte of. 7781 I)iethylstilbestrol derivatives. 776—778. 7781 Dillerin. See Adapalene Ditlorasotte diacetate, 81)81.812 Ditlucaut cc Flucottaiatle t)ttlanisal, 757 Digestise enl.ymes. 4 Digitalis. 656 I)igitalis glycosides. 655—657

l)igittivtn..teteve netabolites at'. l3St Digosin. 656 Dilisdoicodeine, 73), 7))t l)ihydrocotheiite hitaru"ate. 747

developttteitt of. 941 —942 l)tliydrotolie acid. 409—41)). 41111

3581

Diltytlrostreptotttyciut. 337 I)iltydrotaehysterol. 878 Stt'l)ihydrotestostemne biological acttvtty nI, 797, 7981 biosyttthtesis of. 7691. 771). 797, 8(12 ntetatnehisttt itt'. 797. 7981

rn-l)ihydrosyben,cne. 222 Diitvlohydni'cyqitin, 263 Dilanrin. Ste Phenyttdtt l)ilaadid, See Hydrotnorphoite Diloaanide luroate. 261 Diltiazem as atttiarrltyihtttic. 642 as vasodilattir, 629t, 631). 63)11 l)inteultydrinate. 71(3 Dimereaprol. 264 metabolism al, 326 I)itorrcapto- I -propaniel (BALI. ntetabolism 126

Dttuetatte. See Bmatphetttr.tnttne Ditttethuindette tttaleate, 711)

I)imetliisiNain, 694t I -12.5-Ditttethosy—4-methylp(tettyl -2-

atttinopropane. See SIP Dittietlwlbeiveylatnotoniuni cltloride, analog of. 224. 225t Dimethyl suliosude (DM501 in ltiglt-throughpat screening. 53—54 ntetabolisnt ttl. 99. 109 Diatcthyltryptamint'. 521 Dititiprost. 827 Dinoprostotte. 795. 7951. 829 Dinoprost trintethaminc. 829 Di,idoqttin. See Iodtitluinol l)iovan. Set' Valsartan l)iosapht'tyl hatyrale. 7391 Dipanonc. 739t Dipcrodon, 694t Diphemanil ntcthylsttllatc. 585 Diphcttltydrattune. 702-7))) tociabolism til', 85 1)iphentdtil, ntetaholisnt ccl'. 87 Dipltenosylate, 736t, 737, 748 active ittetabolites iii, I 35t ntetabohisnt ttL 109 Diphentotn. -Ste Plteitytoin Diphenylpyraline hydrochloride. 7)12, 7)14 l)iphtheria ttivoid, 21 2t, 214. 215

Dipivelrttt. 5)2 as prodntg. 145. 14Sf bottds. 31t. 33. 331 1)iprivan. See

Dipyridainole, 633 1)ipyrotic. 762t. 763 I)iquinol. Set' lodvtqutnot Diraqmn. See Qtttntditte gluctinate Directed library. 56. 6) I)irit(tnmtycin. 352—353 l)isalcid. See Salsalate Disinleetants, 218—223, 218t chassit)cation cii, 218. 21 8t etTeerivettess oh', evaluation ttt', 239 improper use ct', 219

phenol coefficient for. 221 Disonter. See Deshrontpltettiratttine maleate l)isopyramide. 638 metabolism ttl', 85

968

!,uiet

Dispermitt. Sit' Piper.i,.tne Dissociative anesthesia, 488 l.)ictal convoluted tubule, sodium re.tbsorptton in. 599-6(8). (tOOl Distance-dependent dielectric constant. 934 Disulluram. metabolisnt of, 108. 114 Dilhioglycernl. 264 Diucardin. Set' Hydroflumethiazide Diulo. See Metolacone Diuretics. 596—620. 601—620 of, 6(11—602, 6021 active tubular

adverse elIccts of. 618-619 carbornc anhydr.use inhihitars (site It. 603-605. 6041. 619 combination, 620 concentration of, 601—602 for congestive heart failure. 618—619

definition of. 596 dosage of. 619—62(1

efficacy of. 601—602 entrarcnnl activity cr1. 618—619 for hypertension. 618—619 kaip (high-ceiling) (sitC 2). 601, 610—616. 620 mechanism of action 01. 601 1x,iassiunt loss due to, 618—619 potassium-sparing (site 4). 616—618. 621) potency of. 601 prepardliotis of. 619—62(1

primary action of, 596 properties of. 596 secondary effccts of. 596 stntcture—acth'ity relationships of. 602—603 thiaridc/thiazide.like (Site 3). (,05—6l0. (,O6f, 6061. 607f, 6081, 619—620. See also

Thiazide/thiazide'lilse diuretic' transport of. 602. 6021 Diurexan. See Xipatnide Diuril. See Chlorothia,.idc

DMG.6.mcthyl.6.deotcytetracyclinc tDMGDMOT), 348-349 DMG.mittocycline I DMG.MINO). 348-349 DMSO. See Dimethylsulfoxide (DMSO) DNA tilkylation of. 398—399. 399f antisense, 193—194

cloning of. 164, 166—l(i8 complementary, in combinatorial chemistry. 49

modeling of. 920 reconibittant. See also Recotnbinant DNA technology processing of. 172 production of. 64. 168—169 replication of. 162. 1631 synthesis itf, 162. 1631. 192. 93 pltusporylatton in. 1541. 1551 tnunscription of. 162. 1631 vectors for. 165—166. 1661

DNA hybridization. 166 eDNA libraries. 64. 1641 DNA ligases. 165. 860 DNA microarrays. 192-- 193. 448—449 DNA probes. 192—193 DNAse. recombinant, 185—186. 859t. 861

DNA lags. for cumbinatt,rial Iihr.tries,52—53. 52t rDNA technology. See Recombinant DNA technology DNA viruses. 36%t. 37(lt, 372 Dobutamine, 535 metabolism of, 25. 133 Dobutrex. See Dobutamine Docetaxel. 425. 428 Dofetilide. 641

Dolette. Set' Propoxyphene hydrochloride I)olubid. See I)ifluttisal DolopItinc. Set' DOM. Set' STP DON. 411 Donepczil. 566 development of. 943—944, 9431 i-D pa. as drug delis-cry systettt, 157. 571 Dopanitnc. 524—547 adrenergic receptors and. 527—528 biosynthesis of. 524—525. 5241

gatiglionic stimulation by. 586. 5871 properties ii). 524 site.specillc delivery of. 158. lSX(. 159 structure ol, 524 as sympathotnintetic, 532 uptake and metabolism of. 525—527. 5261 Doprant. See Doxaprum hydrochloride D-optitnal selection. 58 Doral. See Quazepam Dortdctt. See Olutedtiniidc I)ornase aIls, 185, 838, 839t, 859t. 1161 Doreolamide. design of. 921 -922. 9211. 9221. 942—943

Dosttgc. receptor affinity and. 8 Doturem. Set' Catdotcntte mcglutnine Dots on cellulose, in combinatorial svntltesis. 44.451 Double-ester prodrugs, 146—147. 481 Double helix, model of. 920 Dovonex. See Calcipotriene Doxacuritim chloride, 591—592 Doxaphenc. See Proporcyphene hydrochloride Dosaprato Itydrucliloride. 510—511 Dttxazosin, 540—541, 5411, (i52 Doxepin hydrochloride. 517—5111

Doxercalciferol. 879 Doxorubicin, 415, 422—423 l)oxycyclinc. 345t. 347—348 For malaria. 293. 2931 Doxylatnittc succinate. 702, 703 l)ittmantine. See Dimenhydrinate Drixoral. See t..( -f ).Pseudoephedrifle Drogenil. See Flutantide Drolhan.Sre Drotnostanolone propionate l)romoran.Si'e Racemorphan Dromostanulone prupionate. 436 Dropcridol. 51)1

Dropcridol.ft'tttanyl. 738 Drospirettune. 7871. 789

in contraceptives, 79lt Drotrecogin alIa. 185 Drugls of ahttsc. 521) 9—17 acid—base properties activate metobolites of. 7—8

biotransformation tit. See l)ritg metabolism dissolution of. 3 eneytnittic reactions and, 4 hard. 142 ideal, 3

lipophilic. 31.65 definition of, 65 microbial resistance to. 301. 305—307, 335— 336

percent ioni,ation of. 15—16. 1Sf, 161 receptors for. See Drug—receptor interactions: Receptor(s) recombinant. 175—191. See also Recotttbinant drug product.'. sile.spcciltc delivery of. 155—159, 1571— 1591

soft. 142 synthesis of parallel. 43. See also Combittatonal chentistry serial, 43

targeting 3—4 unpalatable. ptsidrug forms for. 145—146

l)rug ttcliott citemical stuctare and, 17—21, 28, 31—41

duration uI. protein binding and. 6—7 isotnensnt antI. 35—37. 3Sf, 361 stattsttcal predictttsn ol, 17—26 Drug allergy. See Allergy Drug carriers. 155—159. 1571—1591

Drug delivery carriers or. 155—156, l571—lSOf of recombinant drug products, 175 site specific. 155-159. 157f—159f Drug desigit. Set' also Drug development advances in, 1—2

avittlable inlormatton in. 55—56 calculated conformations in, 37—38 classilicalioit techniques in, 24—26 combinatorial chemistry in. 26—27, 43—63. See also Conihittatorial chemistry cotitputer.assisted, 27—41, 919—945, See tutu Conipuler.ussisted drug design

cottformational Ilexibitity attd.34—35. 341 database scarchtng in, 39—4(1. 55—56. 93(1—933

de novo, 55 drug distribution and. 9 drug tnctabolism in, 135 drug—receptor interitemions and, 9, 27—37 Sec aIrs, Drug—receptor interactions

energy diagrunts for. 37 Free.Wilsoit analysis in. 23, 26 goals of, 17 graph theory itt, 23—24. 24t. 2Sf identity variables to. 23 irrational, 26 isosteflsiii in. 40—41, 411 kits for. 37

I.ipinski Rule of live in. 40. 55 molecular mechanics in, 31) ttit,lecular modeling in. 27—41 uttiltivariute statistics in, 24—26 optical attd. 35—37. 361 overuiew 1—2 QSAR studies itt, 17—23. See also QSAR studies

quutttuttl itieclianics in. 38 rational, —2, 919, 94(1 receptor isolation and, 28 tvgressiott analysis itt. 24 scettarios for. 55—56 screening Screening statistical methods in, 17—26 stereochemistry and, 3l—34,32f, 331. 35—37. 361. 37f structure-bused, 55. 939—944 stntcture-ftinction relationship and, 17—21. 28

substituent libraries in. 26—27 sttbstitaettt selectiott itt. 22—23. 231. 25 topological descriptors in. 23—24. 24t training set in. 25 web sites for, 41 u.ray crystallogruplry in. 37—38 Drug developmettl. See also Drug design hiotechitology in. 160—162. lb2f, 169—172. Set' also Biotecltnology

DNA tnicroamlys in. 448-449 proleotitics in. 449 l)rug distribution, 3—9 bltiod—brnin harrier and. S drug metabolism and. 7—8 excretion and, 41. 8 with intravenous tdttiinistr.ttii,n. 41, 5 mecltanisttts oF. 41

Index mtxtilicatuon 9 with oral administration. 3—5, 41 will, parettter.il adtitinistrutiun. 41. 5—f>

plc aid. (6—? placental harrier md. 6 protein binding in. 6--7 tissue depots and. 7 tr.ttlsport ,,iechanistns in. 41. 5 Drug—drug interactions cotnputer'asststed drug design and. 944—945 cytochromc P-450—based. 131St. PSI ericyine induction in. 1301. 131 Drug excretion. 41. 8 Drug—food intermtctions. 1311. 32

computer.asisted drug design and. 944 -945 Drug Intentiation. 142.5cr also Prodrugs Drug-like molecules. combittatorial synthesis 01. 46—4K. 461. 471

arotnalic hydruxylatiiin in,

Duration of action, protein binding and. 6-7 Duricel. See Cefadroxul

111—126 4>1 prmmdrugs. 142—144. 1431. 1441

Dymclor. See Acctohexumtde

product utereouclectivity in. lOS. 132—133 of r.mcernic tnixrures. 132 of recombinant drug products. 175

701, 721.

741. 93

1121

of sulfates. 115—116

cytochromc P-45(l enzymes in. 66-69. 681. 691.91. 129—PSI, 13t)t in drug design. 135 enzyme induction in. 131)1. 131 enzyme initihition in. 131—132. 131t lirst.pass effect in. 67 foods 1311. 132 lunctionalization reactions in. 65—66. 651.

69-Ill

general pathways of, 65—66. 6ot in. 129. 193 genetic

glutailtionc in. (>6. 73. 98. III. 117—121. 1191 hcpatuc. 7—8. 1,6—6K

hereditary liieii,rs in. 12') hydrolysis in, 109—Ill of esters and aiiiides. 109—11(1 intestinal. 1>6. 67

mcrcapluric acid in. 117-121 niethylalion in. 125-126, 1261 monoamine oxidases in. 90—91

N.acetylation in. 93 nutritional factors in. 1311, 132 overview of. 65 oxidation in. 69- 103 of alcohols and aldehydes. 99—101 01 aliphalic and alicyclic carbon atoms. 81—84

Ut allylic carbon atoms, 77—81 of aromatic moieties. 69—74. 701. 721, 741 at heneylic carbon atoms. 77, 771 at carbon atoms a Ii, carbonyls and imincs, HI in carbon—nitrogen systems. 84—911

in carbon—oxygen systems. 84. 98 in carbon—sulfur systems. 84. 98—9') cymochromc P—ISO enzymes in. 66—69. 661. (>81. 691

deamination in. 89 de.sulluration iii. 99 genetic lactors in. 129 N-dcalkylanon in. KS 0-deulkylation in. 98 of oletins. 74—77 rate of. 129 S-dealkylation in. '38—99 of ertiaty aliphutic and alicyclic amines.

Dutustcnde. 802—803. 8021, 8031 Dyazidc. See Triamtercne.hydruchlorothiaeide

Dyclonine hydrochloride. 694t Dyes. 227—228

sulfonamide iso, 269 Dynabac. See Dirithromycin DynaCirc. See Isradipine Dyrenium. See Triamterene Dymirhyihmtns. 634—636

rrductim,n in. 103—109

of aldehydes and kctone carbony!s. 103-- 107

of nitro and azo compounds. 107—108 rcgioselcctivily in. 133—134

sites of. 66-67

conjugalion in. 8.65—1,6.651. 111—126 of glucuronic acid. 112—I IS. I 12f—1141.

66—69. 1,61. (.1)1. 691

oxidalivc aromatization in. POP oxidatixe dehalogenalion in. 101—103 oxidative dehydnigenalion in, 101 pharmacologically active metabolites and. 134—135. l35t phase I reactions In. 65—66. 651. (>9— III phase II reactions itt. 8. 65—66. 65t.

semi differences in. 129—13(1

l)ntg metabolism. 7—8. 65—135 acetylution in. 121 —124. 1231 ageand. 126—128

969

in smokers, 131 species and strain differences in. 28—129 stereochemical aspects of. 132—134 smthstntte stereoselectivity in, 132 Drug metabolites phammacoktgically active. 134—135. 1351 toxtcity of. (>5 Drug partitioning. 18—21. 191 n-octanollwnter system and. 19—20 partition ci>elliciemtt and, 19—21 l)rug—raceptor interactions. 3. 8—9, 27—35

active-site—directed irreversihlc inhibition in. 29

agonist/antagonist actions and, 28—29 biological respoitse in, 29—31. 311 botids in. 29—31. 311 computerized images of, 922. 9221 drug design and. 9

efficacy and, 572 flexibility in. 28. 34—35 functiminal groups in, 28 intrinsic activity and. 572 molecular structure and. 31—41 optical isomerism and. 35—37 Puton rate theory of. 572 protein conformation and. 28 range of. 28 receptor asymmetry and. 35-37 receptor locaxion and. 28—29 receptor properties and. 27—29. 291. See also

Receptor(s) side effects and. 9 stereochemistry of. 31—34 variability in. 28—29 virtual scteentng for. 55 l)nmg.reststhni patlttmgenm.. 301. 3(15—31)7. 335—336

Drug screening. also Cumputer.assistcd drug desigtt ol antineoplastic agents. 392—394. 3931 automated. I biotechnology in. 170—172. 1731 Itetetulogous expression and. 170—172. 1701 high-throughput. 26—27. 40. 401. 43. 53—5-4, 541

human.tumor.colony—forming assay for. 394 random. 1—2 reporter genes in. 171—172

virtual (in silico), 54—55. 56.419.919 xenogrmtft models for. 394 DTIC. See Dacarbazine

Ducarbazine DTP vaccine. 2l2t. 215 DTIC.Dmmme. See

Dundenal ulcermi. 718—719 l)ur,mbolin. See Nandrolone

Duracillin. See Penicillin 0 procaine

E

0.64. 447 02020. 566 EA 713. Srs. Rivassigmine Easson-Stednian hypothesis. 530. 5301 East African sleeping sickness. 260 Echinacea. 905—907

Echinocanadins. 246 Echothiophate iodide. 569 Econazole nitrate, 24! ED,0. 17 Edecrin. See Ethacrynic acid Edrophonium chloride. 567 EES. See Erythromycin ethylsuccinaic Efavirene. 383—3114

Effexor. See Venlafaxine Eflomitlitne. 262—263 Efudex. See 5.F!uorourueil Eicosanoid(s) approved for ltuman use. 827—828

biological activities of. 820. 822t biosynthesis of, 8 18—822. 8191. 820f in clinical development. 824t—$25t. 829 design and developmetit of. 823—825, 824t—825t

discovery and development of. 818 drug action mediated by. 822 nietabolism of, 821f, 822 moditicattons of. 823 ophthalmic, 823. 828 br veterinary use. 828—829 Eicosanoid receptors, 825—827, 826t F isorncrc. 32. 321 Elavil. See Anutriptyline Electrolytes, renal reabsorption of. 596—601. 5971—6001

Electromagnetic rudialion, 454 Electron capture decay. 456 Eleclron population analysis. 939 Electron volt. 454 Electrospray ionization. 52 Emcyt. See Estramustine Eznetine. 261—262

Empinn. See Aspirin Emprostil. 8241 E.Myein. See F.rythrumycin Enalapril. 646. 647f. 647t as prodrug. 5 Ennlaprtlie acid, 5 Enbrel. See Tumor necrosis factor, recombinant Enclotniplmene. 781

Encoding, for combinatorial libraries. 52—53. 521. 52t

Endocytosis. viral, 37! Endometrial cancer, estrogens and. 779. 787 Endometilosis. 801 Endoncunum. 680, 680f Endorphins. 744. 843—844 Endothelium.derived contracttng factor, 552 Endothelium.derived relaxing factor. 552 Enduron. 620 Energy diagr'.uns. 37. 371

970

I,ukv

Energy minimization. 929—930. 934 Energy Icons, in molecular ntecltanics. 38 Enflurane. 486 See Hepatitis B vaccine linisoprost, 824* Enkephalins, 744. 843—844 Enols. gltlcUronidation of. 14 Enoxacin. 24$, 2.1St, 249 lnIa,nr,vlai lti.iW!vrica, 259—260 Entocoti. See Budesonide En,actin. See Tnacelin linayme(s), 835—841)

catalytic activity of. 835—837. 8361. 8371 classification of, 831) conformation of, 835

definition of. 835 flexible. 835 heterogeneity ot.

69

induced-fit theory for. 835 products. 838—840, 8391

proeniyines and. 837 recombinant. 183—86 secrelion 01. 838 specificity of, 836 structure and function of. 835—837, 8361. 8371

synthesis of. 837—838 ,.yrtiogens and. 837

Enzyme induction. 13th. 131 Enzyme inhibition. 131—132. 835 Enzynie.substrnte complexes. 835. 836 Eosinophils. 198 Liovtst. Ste Gadoxetic acid Ephedra 905 911—9l2 Ephedrine. 538.538t metabolism o1. 107 Epidutail anesthesia, 6117. Set' also Local anesthetics Epilepsy. 503—504 Epinephrinc. 524—547 itdrenergic receptors and. 527—528 biosynthesis of. 524—525.5241 in local anesthesia. 68$ ocular delivery of. 1514 prudrug forms of. 45. 14Sf. 151)

properties of. 524 structure of. 524 as sympalhomintetic. 532 uptake and metabolism of. 525—527. 5261 Epincuriuni. 681 Epirithicin, 416 Epitestusteronc. structure—activity relationships for. 7914—799, 7981

Epitctracyclines. 342, 344 Epilopes. in combinatunal chemistry. 43. 62 Epilope tagging. 169 Eplerenone. 619. 815 Epoetin alIn. 177—178. 8591. 862—863 Epogen. See Epoctin alfa

kpopnrstenol. $23 Epoxide hydruses. 73 Epoxides, Iortnation of. 74—77 Epiiftbatide. 634 Eqttanil. See Mcprtihnmate liquntitrial conformations. 931. 9321 Equilibrium potential. 682 Equiliti sodium sulfate, structure of. 7771 See Ivermectin Erectile dysFunction. 29 Ergocalciferol. 875 preparations of. 877—878 Ergosterol. 877 in lipid membrane. 231, 2321 Eaypar. See Eryibromycin stearaic F.ryl'ed. See Erythroinycin ethylsuccinatc

Erythrityl tetrnnitratc. diluted. 625t. 626 Eryihrocin. See Erythromycin Erythromycin. 3001. 349—351

Esirunmule. See' Cloprostenol sodiutti F.taiiercept. Set' 'l'utnor necrosis lactur. recombinant

Erythroinycin estolate. 350 Erylhromycin ethylsuccinate. 350 Eryihromyctn gluceplatc. 350 Erythromycin lactobionate. 350 Erythromycin stearote. 350 Eiyihropoiettn alfa. 177—178. (462 P. (Taft's stenc parameter). 21 E.scrine salicylute. 548 Esidnx. See Hydrochkiruthiaztdr Eskalilh. See I.ithium carbonate Eckazole. See Albcndazole Esmulol. 544. 5451 E.sontepntzolc niafinestuun. 722. 723*, 724 Esurubicin, 416

Ethncrynic acid. 613-615. 6l4f. 620 metabolism of. 120 Etltanibutol, 254. 256 Ethanol. 219—220. Set' ala., Alcohols deltydrated. 220

Esters

Ethinyl estradiol 3-methylenc, structure of,

intolerance to. cepltalosporin-related, 325 tnechanismn of action of, 684 Ethanolamines, 702—71)4

Ethchlorvynol, 495 Ethinvl estr.mdiol. 780 as antineriplastic. 433 it. contraceptives. 7911—793*. 794 metabolism of. 71) structure of. 7771

hydrolysis of. 109—110

as prodrugs. l44—l49. l45l—l49f ljstradii,l, 775. St'.' also Estrogen(s) biosynthesis of. 7691. 770. 783. 7831 metabolism of. 775. 7761 preparations of. 779—780 receptor binding of. 782 of. 7701

structure of. 7771 Estradiiil bentoate. soluhility of. 7701 Estr.tdiol cypionate. 793—794. 793* Estrumustine. 437 as antineoplastic. 434 as mutual prodnig. 142—l43. (431 Eslratab. See Estrugen(sl Estnol. 775. See also Estrogen(s) tnetabolism of. 775, 7761 preparations of. 781) structure of. 7771 Estrocytc. See Estramustine Estrogen(s(. 775—785 antic%trogens. 781—783. 781f as antineoplastic. 433 aromatase inhibitors, 7143—785, 7831, 7841 biosynthccis of. 7691. 771). 775

for breast cancer. 779 breast cancer risk and. 433—434. 783 conjugated (equitte). 775. 776, 7761. 7771 preparations of. 780 in conlraceplives. 779. 790—794, 79lt—793t tlietltylstilbestrol derivatives, 776—778. 7771 cndogettous. 775—776 esterified, 776. 7771 preparations of. 78(1 in hormone replacement Iherapy. 779, 787. 796—797. 79th. 7971 metabolism of. 775, 7761 phyiocstrogens. 7781 products. 779—781

7771

Etltiodol. 482, 4821 Ethionatnide. 254. 255 Elhtno,ine. See Morictzinc Ethoheptazinc. 7371. 738. 748 Ethopropazine hydrocltluride. 585—586 Etltosuxitnide, 506 metabolism of. 142 Ethotoin. 505, 5(1St Ethranc. See Enflurane

Etliril. See Erythrontycin stearate Ethyl 4-amtnobenzoatc. 6711 Ethyl alcohol, 2 19—220

Ethyl chloride. 690 Etltylenediamines. 71)4—706 Ethylene oxide. 22(1

Ethylntorphinc. 7331 Ethylol. See Anmilostine Ethylparahvit. 229 Ethyl p.hydroxybcnzoatc. 229 I 7.r-Etliyltestostcmne. 79gm 2.Ethylthioisonicotinaniide. See El(tionamnudc Etltynodi.ml diacetale. 7871. 789 in contraceptives. 791, Etidocaine. 690—693, 6921

litodolac. 760 Etontidatc. 487—488 latonilazene. 741 Elonogestrel. 7871. 789, 793t. 794 Etoposide. 426 Etozoline, 615—1.16. 6151 Etretinate. 873—874

halI'liIc uI. 6 Eucainc, 677. 6771 liucairopine hydrochloride. 580—581 Etufles. Sec Flutamidc Eugenol. 222

Eulexin. St'. Flulatnide Euprocin. 694t

for prostate cancer, 779 pyridoxinc and. 893 receptor binding oF. 777 selective estrogen receptor mixlulators.

Ettmax. See Cru,tamiton

781—783. 7811 sleroidal. 776. 7771—7781

Excretory urogruphy. 478 Exeldemt. See Sulcunasotc nitrate Eselon. S.'.' Rivasligmine

structural classes of. 776—779. 7771 structure of. 7771 therapeutic uses for. 779 tryptophan metabolism and. 893 Estrogen receptor antagonists, 781—782. 7811 Estrogen receptors. 773 Estrogen replacement therapy. 779. 787. 796—797, 796,, 7971 Estrone. 775. See ala.. Estmgen(s) biosynthesis of. 7691. 770. 783, 7831 metabolism of. 775. 7761 preparations of. 780 structure of. 7771

Eutaittide, 26t Evista. See Exalgin, 76(1. 761*

Exetutcstane. 438, 784, 7841, 785 as antineoplastic. 435 Esna. Set' Benzihinzide Extended insulin zinc suspension, 1451. 851,, 852t

Eye. drug delivery to. 15%

F

Factor VIla, recombinant. 665 Factor VIII, 664t, (.65, 863

Index reconihiaattt. 167—168, 184—185, 665, 8591. 863

Factor IX, recombinant, 385. 665 Fameiclovir. 378 Famotidine. 7391, 72)8, 72! Fansidar. See Sitltadonitte•pyrittte:Itaiutiute Fareston. See Tnremtlcne Farnesyl translerase inhibitors. 440 Faseicles. 680, 6801 Faslodex. Sic Fatvestrattt Felbantate, 507 FeIlssuiI.Se,' Feihamate

Feldenc. Sit' Piroxicam Felodupitte. 63! Felyprcssin. 688, 847 in local anesthesia, 6811

l.etroeok

Flutorohutyrophetuones,5181 —501 5-Fluonucyuuusine. 235, 2351

971

staggered tu'rsion angles itt. 92$ Taylor series espatusioti attd. 925

Flttorotitetholone, 81)1, MIII. 812

Fctrhistal uitzuleate. Sit' Diuttetltindetue otaheate Forntaldeluydc strIation. 221)

l'luor'l)p.Sn' Fluorotttethu,lone Fluoriupte.s .5.'.' 5-I-luorucuracil Ftuoroscopy. 454. 4551 5-l'lttonuuracil. 44)5—4)37, 4(8.), 412—413

Formalin, 22:)

screetting data br, 393) Fluorous phases. cotttplementary. in

Fuirtuirtenil. 536—537 ltctrabtydntfitlic acid. 4111, 41111 Firtlan ('elta.'udinte surduutrt

Fu,onajtilid, 76)). 7611 lortutestatue. 7114, 784)', 785

cotuthittatoriat chetuuistrs'. 49

Fluutroxidittc. 406 I'litothane ci' Ilalotluane Etuosetine. 538 Fluosytttesterone, 7991 8111

Foscanuet sodinutu. 379 Ftuscavtr, .Su'e Fosc;urrtet sodiuun

Fluphuetuaciute hydrocltloride. 499t. 5)8)

Fosuuuidcrtitycin. 2'Nt:. 297— 298. 2971 Fttuir-cttropuutueutt t.Igi reaction. 4t), Sill

Ftusl'otttycin trurmethanrinc.363—36.l Ftrsititupril sodiutti. 6471. 647u. 648

Flurandrenolide. 832 rcltttis'e :tctivity oh, 83$): flaracepam, 492

Fenflununtine hydrochloride. 533—534

1"liurhiprucleuu. 759 l:luur(,seue toetahx.hisuut oh, 77

Fourier transt'ontu infrared spectroscopv. iuu cotutbittatcurial clut'tiuislry. SI Free eutergy pcrtttrhatitrut I FUll cahculatuotts. 934—935, 9341 atuatysis. 2). 26

Fenofubrate. 6611

Fltttantide. 436—437, Mill —8(42. 81121

Fruug seutcuttus. $35

Femhd. Sec Hormone replacement therapy Fetnstat. See Butocotuacok nitrate

Femum, Sue Ixrro,ok

Fenoproien. nuetabolistn of. 114 Fenoprolert calcium. 759 Fentanyl citrate. 737:, 738, 74:. 748 501

Feridex. See Feruntoxides Ferrixan. 477 Fernihentoglohin. 858 Femrnwgnelic substances. 476 Ferumonides, 477 Feruunoxtran, 477 Feverless, '11)7—91)8

Fexoleutadine, 9. 712—713

Fibrinogen. 663, 664. 6641. 66$t. 665 Fibrinogen receptor. 633 -634 Field blocks. 687. See n/so Local anesthetics I'ulgrastim, 178—179. 43)1, 433, 859t. 863 Filtration assay, in high-throughput screening. 54. 541 Finasteride, 802—803, 83)21, 8031

First-pass died. 7. 67 Fish liver oils, sitatutin A couutent of, 868t, 869 Five-atont nile. 557 Flagyl. Sic' Metronida'.'ole I-LAMP. Ste Fludat-abine Flasoperidol. 439 Flas'oprotctns. 89(3—893

Flanedil Sn' Gallatittne trieultiodide Flecainide acetate, 643) flexible conFirmation. 34—35, 341, 9311—933 l'loecutatuon, 175 Flolan. See Epoprostenol Flomas. See Tatnsulosin

Set Flaticasone propionate Florinet acetate. Sue Fludroeturtiscune acetate

Floroptyl Sir Isotluorphate Flovent. See l"Iuticasotue proptotuatc Floxiuu. See Oflcuxaciu

Flosuridine, 433 Flucinom. See Flutatnide l'luctunanule, 244 Flucytosine. 235. 2351 Fludara. See Fludarahine

l'ladarabine. 405.432 fiudrocortisone acetate, 81)71,8)68, 811 Flugerel. Set' Flutamide flukes, 265 Flutnadine. See Riuuiantadune

Flutnaeeail. 487, 489

flunisolidc. 8:2. 834, 814t Fluocinolouc, 809: Flutucinolone acetiunide. 8ht8L 809t. 8:2 Flaociuonude. 80')t Fluorine radiopharnuaceuutucals. 468

inetalsidistut iii, 1)4

F:or,ulut eu 'legal uur Full sahol. 755 Fntvestrauit. 7811. 783

as autineoplastic. 434 propionate. 812. 814. 8141 Flus'astatuut. 663

Fnncugulliut. aittiticopltustic activity of. 447

Flusestrant, 781, 7811 Flavoaantine.5 19

I'unctuoru,ul espression cluiuttng. :66— 67. 1671 Functuusnal genontics. :92. 1921 Fnutctiotuali,atiuuit reacsuutus. itt dnig

FML. Set' Anitrotitetliolone Focused library. 56. 61 l:olacine Sit Folic acid

tutetal,uulusru. 65—1,6, liSt. 69

Folate antagiuttisus, 4118—41)). 41111

l'ttngacctin Sue 'I'rrztcetin

Folate cocntyuoes. sttlfonantide.s and. 27)) 27:.

Fangal ituiectituns cntaiuetnus. 231. 2311. 232:

2731—2731

Folate redactase iuthihiittits, sullottztttuides arid.

topical ageutis h'uur, 233—235 uuppofluunistuc. 23)1—231

275

sabcnt&uneiutis. 231. 232t

Folic acid. 896-898 dietary sources of. 896 discosery ol. $96

superficial. 231. 232t systcuuttc. 23)). 232t tissue response to, 231—233 Futtgiiauue. Sue Auttphotericun 34 Furaciu.S,'t' Nitrtul'unu,t,urc

nueuaholisot ith 896-897 vitamin lb. and, 896—897 products. 897-898 structure oh. $96

I:uradauttuiu

Fuulic acid ,utttagonu.sl.s, 897

Folk acid derivatives. antineophastic. 4118—411), 43111

follicle—sttutuulatittg htontttituc FSH

Ill

—775.

7741.841,844 rectutnhitiaitt, 176

ci' Nitrtrhuurauutttitt 'Sri' I)ihtisautudc tnruuate

Furanuttidiunc 252. 253 l:utrosetutide 269. 61 l1—(r 13. 6111. 62)) Furoouune.Su'u 1-urantutidotuc Fttsiutn poutcins, 13,8 — I 69

in drug screening. 172

Follistint. Si',' Follitropin beta Follitroptn alia. 77 Follitropin beta. 377 Fuuls'ite. See Folic acid

Fiitttocaiite 694t I:iK4.dt-Jg iuttcnuclions. I) It. 132 cotttputcr-assisted dntg design intl. 944—945 Foradit. Sit' Fortttoteroh l:i,r&unesu.c. lsot)uraue l:u,ree field ntethtods, ')2)—')2'). See cc/ic, Compater'assisted doug desigut

G6PD, tttataria and. 283, 288- 289

(;AIIA. 485, 489 (3AIIA5 rccepuuurs. 485, 489 for auutcottsulsaruts, 51)4 Iuur autsiutlytics. sedatise. and hypnotics. 488, 489

br gcncr& ztttcstltettcs. 485 Gahapenlin. 51)7

hall-attd-s3trittg uttodels and. 923-925 t'ouloutth's law and. 927. 9271 cniss-tertns and. 929 eclipsed torsion angles and. 928 Fourier series attd, 928 harntonic appronunuatton attd. 925 umpnuper torsion atugle concept rod. 926 I.ennard-)ones potential aitul. 926

(iahttrul Sit' Tuagahtne

MM2 Fuce field antI, 927

Gadoversetattuidc. 476 Gadius'ust. Set' (hitlitlrnuriul (iadoseuic acid. 477 (Jalantamtne,Srr7 Gallatutunc trieultiodide, 591. 592—593

MM3 Force Odd and. 925—926, 927 MM4 force held stud. 925—926 MMFI"94 hiurce field attd. 925—926 in mculeculttr dyttautuics sitttultttions, 1)33 —939

Morse cnn-c attd. 925, 9251 quadratic equaticutis ut. 924- 925 restricted ottation and, 928

Gadohretuaue ttuegltuntutie. 477 tiadohuttruul. 473, Gaduudianuide. 476 Gad.ulituiuutu dtuuttrast agenus. 476 (iaduupcnteuutc ditttegluuuuituc. 476 (iuudurtcnute megluututrnc. 476

(Jadoteridol, 476

(Iallituiuu uuitratc, 43(4, 432 Galliuuruu ntdiurpht:trotaceuticals. 468

Ganterocytes. P/ut.orttn/inot. 284

972

Inde.t

Gamma scinhillation ca,TKr.i. 458—46(l. 4581.

Gatuophen.Sts' Hexachlorophene Ganalol. Sec Suliameilursa,,,k Gancirlovir. 377—378 Ganglionic hhiwking agenl.586—58') dcpol;iroing. 587—588 nondepolariring competihise. 587—588 nondepolauleing nonctimpelitive. 588—589 rgan-specilic eltccts of. 587. .S87r Gatiglionit' stimulation. 586—587. 5871 ((anile. See Gulliuuii nitrate Garamycin. Sc,' Gentamicin Garlic, 91(1—911

Gustnc enrsmcs. 4 Gastrix inhibitory pephide. 1)55

Ga.rh, mucirui. acid seereliun by. 7(8. 711(1 Gastric ulcers, 7(8—7(9 Gastnn. 854 Gastruinlesilnat Itoriutones, 854—855 Gastroinheslinul studies, 480—4441, 481)1 Gastrointestinal tract

it drug distributitm, 3—5. 41 hiwer, drug delivery K). (58 gaui-he conformation. 32, 33 Gaudier's disease. 186 Gaussian hype furntions. 937 GDP-hinding pauheins. 550. 552 Gelatin. 834, 8341 Gelatin flInt, 834 Gelatin sponge. 835 Ch!lIhIni. Sts' ((claIm

Gernian violet. 227

1dm

(h,lloatn. See Gelatin sponge Gemeitahine, 41)7, 413 Gcmeprvva. 8241 Genuiibro,iI. 659—660 Gemtui.umnah ouogzinhicun. III') liv antini'oplaslic. 4.13 Gemini. Ste Geuncitabiute GeutBank database. 16(1. 1611 Gender. doug metabolism and. 12')— 13(1

Gene(s). (62 cloning of. 164. 166—168. See also Cloning reporter, in drug screening, 171— 172 Gene capresalon. 167— (68 anhiscnsc oligonucleolides and, 193—194

definitiiun of. (92 helersilogous. (68 protcomics antI. 193 in recombinant DNA technology. 167—161) Gene expression systenus. 167—168 General anesthetics. 485—488 inhalational. 486—487 intravenous. 487—488

Generic library. 43. 441 Genii.stcin, 438

Gene therapy, (94 Genchic algorithms. 58. 61. 933 Genetic cloning. Sc,' Cloning ((cnetic engineering, (62— 166. St', also Recombinant DNA technology steps in. 858—86(1

Genetic factors, in drug metabolism. 128—129. 193

Gene translcr. (94 vectors in. 165—166, 661, (68 Genislein. 778—779, 7781

Geometric issiuners. 32 Geopen. See Carbenucillin disodium Germ cells. tr.tnsgetues in. 194

Geniticides, 2(7-223. 2 2181 classification of, 2(8. 2181 ellectiveness of. evaluation of. 219 improper use of. 21') phenol coeFficient for. 221 Giurdiasis. 261) (;ümkg,, biloba. 9(2—913 Ginseng. 913-914 CIa. 883—884. See also n.Carbmvtyl—glutamic acid ((Ia domain. 1)83

Glaiidular tnascariuiic receptors, 552 Glass hearts, in combinatorial chemistry. 49. (ii) ((leevec. See Imatinib (3Iiiil cells. 679 Glicluiide. ('711

(ilimepiride. 670 Glipieide. 67(1 metabolism of. 82

Global minimum, calculation iii, 37 Globin line iuistilimt suspension. 851 t, 852. 852t Globtiluns, 8331 Glomerular filtration. 596—601. 5971—6(8)1 Glossary. cml comnl,inatorial chemistry. 6(1—63 C,lucaGcn. Se',' Glucagon. recombinant Glucagon. 853—854

recombinant, (75 Glucocturticiuid(s). Sc',' ,ilxo Sleroid(sl as antineoplashics. 435 Iuiulogical activities uI. 18)6 hiosyitthe.sis of. 768—77(1. 7691. 804—805.

804f coiitramndicutiumns ii). Ml))

deficiency of. 805 inltnuuitssupprcssant activity ot. 81)6 inhaled. 813-815 nietabolisni of. 805. 8051 wtth salt retention. 807-8(18. 1)071—8081. 811 niodifucations of, 8(16—8(17. 8l)6t uiphtltalmic. 8l1)—%l I, 11111 product.s. 8071—808f. 811—815

relative activity iii. 8(19, 8(1)1 resistance to. 806 structural classes of, 8(16—8119

structure—activity relationships for. 8071—8081. 8011—809. 809t

structure of, 81)71

tapering of. 810 therapeutic uses of. Ml)) with very low-to-absent salt retention. 808—809. 811—812

Glucocorticoid receptors. 773 Glucophruge.St'u' Metlormiu dehydrogcnasc

deficiency. maluria and. 283. 288—289 Glucose metabolisnt. insulin in. 850 ta-Glticosidase inhibitors, 672—673 Glucoside prodrugs. 158. 1591 Glitcoleol. Set' Glipiiide

Glutamine. conjugation of. 116—117. ((61 Glutaralilehydc. 2211—221

Glutathione acetatiminopluen toxicity arid. 96—91)

conjngationoi, 117—121. 1191

tna'tivalion of, 336

Glyset. See Miglitol GnRH. 774 GnRH agonists. with antiatidrumgen.s. 81)1 Gimnadoliberin. 1)41 Gimnadotropic hortuuimnes. 844—845

Gonadoiropin.releasing liorutiune (GnRIlL 774. 7741. 841 Gtmnadiuiropins. 773—775. 7741

(iimuial'F. See Follitropin alla Goserelin. 437 with antiandrogens. 1401

GPllli/IIIA receplors. 633—634 C proteins. 551). 552 in vision. 871 G.quadriplexes. 448, 4481 GR-175737. 728—72'). Gramieidin.359—36(t Grain-negative bacilli, drug-resistant. 31)1 3(15—3117.335—336

Gr.inutiucyte ciulony-stintulating factor. recumbinatil, 178—179. 863 Granulucyte.mnacrophage colony.stitnulauirg factor, recombinant, 179 c;runitliwymes. 197.

981. 2)1))

Grapefruit-drug interactiiitts. 1311. 132 Graph theory, ut drug design. 23—24. 241. 24i GRAS list. Gray baby syndrome. 115. 126 Grid searching. 932

Grilulvin. See Gns'olulvin Grisactin Sc',' Griscofulvin Griseolulvin. 238. 3001

Gris-PEG. S,', Griseufulvin Growth Imorntimne. 1(44

recombinant. 1611. 175—176

Growth hormone receptor, cloning of. 172 Growth-releasiiig factor. 841 CT functions. 937 G'l'P-hinding proteins. 551). 552 (4uanaben, acetale. 534. 653 Gttauadrel, 529, 651 Guanaiole. 428 Gttancthidine. 529, 651) Guanfacinc hydrochloride. 534. 653 Guantne. alkylation of. 398.399. 3991 Guanosine rhiphospliate )GDP)-binding priiteins. 552 Guanosine niottophospliute )GMPI, in smooth muscle relaxation. 2641. 623—624

tripliosphate )GTP).bindiflg proteins, 550

((-WellS,',' Lindane (iyne.Lomrmntin.Sm'e Clolrtnsa,olr

Gluctimnidali,itt. 112— 115. 1121—- 1141. 1121

Genomic libraries. 164, l64t

Gentanticin. 3411

916—917

Gly-Oxide. Si',' Carhanmide peroxide topical solution

Guancthidiuue uttonosullate. 651. 6511

topical, 81)9—81(1. 8119t

Genomics. 191—193 hioinIormuatics and. 191 —(92 DNA microarrays and. 192— (93 in drug development. 448—449

functional, 192. 1921

t- Glyburide Glyhundc. 67)) Glycine. conjugation of, 116—117. 1161 P.glycopri8eins. in drug resistance. 392 Glycopyrrolate. 581 Glycyctines.348—34') ((h-ct rrlmi:u glahra var. typic,c (licorice), Glyass.

Grocillin See Carbenicillin indanyl sodium

4591

in drug nietubolisnt, Wi, 73, 98, III. 117—121. 1191 Glutuhliiutnc

Glutelins. 8331 Gluteilmimide. 495 metabolism uI, 82

recombinant. (69

U H, receptors. 691) H1 receptors, 69)1—69') H3 receptor antagonists. 727—73(1

H, receplors. 699, 727 receptors. 699 HA acids. 15—16. 61 !Iuu'imtoplmiltcs mnflue,:znc vaccine. 2121. 214

Halaiepam, 491 Hala,vonc. 224

Index 812 Hukion. See Triaro}am Haldol. See Halopentlol Halfun. See Ilalofautinne Hallucinogens. $-amylamino. 520—521 Halobctasol propionate, 8081. 812 Halofantrine. 293—294. 293f. 2961 Halogen-containing germicides. 223—224 Halopcridol. 501 Haloprogin. 234 Halcinonide. 14(1141.

Halotestin, See' Fluoxymestcrone

Halotex. See Haloprogin Hulothane, 486

metabolism of, 11)1 Hainmeu's constant I'll). 2), 211 Hand washing. importance of. 218-219 Hard drugs. 142 Harmonic appronirnatiou. 925 Harmonic simulations. 935 Hartrcc'Fock lImit. 938 Hiuruee-Fock-Rootbaan equation. 938 Hartree-Fock wave (unction. 937 Heart disease. ischemic. 622—623. 6231

Hectorol. See Doxercalciferol Hedeoma pulegeoidts (pennyroyal). 915 Helicobacier priori. 719 Helixate. Sri' Antihemophilic (actor. recombinant Helminthic infections. 264—265

Helper I cells. 200 Hemnabate. See Carboprost trometltamine Hematopoiesis. 177. 1781. 197. 1981 cytokines in. 77, 1781 Hematopoletic factors, recombinant. 862—863

Hematopoietic growth factors. 177. 1771 reconubinant. 177—179. 1771 Hemoglobin. 857—8514

Hemoglobin C, malaria and. 283 Hemophilia. recombinant clotting (actors for. 167— 168. 184—185

Hemophilia A. 665 Hemophilia B. 664 Hemophil M. See Antihemophilic factor Hendem'.on-Hasselbalch equation. 13

Henle's loop, sodium reabsorption in. 598—599. 5991

Heparin endogenous. 665 pharnuceutical. 667 Hepatitis A vaccine. 211—213. 2121 Hepatitis B vaccine. 1146. 2121. 213. %59t. 8601 Hepatitis C vaccine, 213 Hepatitis E vaccine, 213 Hepatocatcinogenicity. of amides. 96 Hepatotoxicity of acetaminophen, 96—98

of bromobenrenc. 73-74 Herb(s)

definition of, 905 as food additIves. 904—94)5 Herbal medicines. 904—917

active ingredients of. 905 adulteration of, 905 appeal of. 904 for cancer, 424—428, 915 chemisuy of. 905 elassthcation of. 904 drug properties of. 905—906 GRAS list and, 904—905 historical perspective on. 904 purity of. 905 regulation (if. 904—905 standardization of, 905 types 01. 906—917 Herceptin. See Trastuzumab

Heroin, 731. 733, 745 Herpesviruses, 3701, 372

Herplex. See Idoxuridine Hetacillin. as prodrug. 143—144. 1441 HETEs. 820. 1422m

Hetrazan. See Diethylcarbamazepine citrate Hexachlorophene. 221—222 2.4-Hesadienoic acid, 230 Hexaeehyltetraphosphnte (HTEP). 569—570 l'lexahydropyrazine. 265 Hextilen. See Altretiunine Hexalgon. 739t Hexaniethonium. 588 Hexamelhylcnetemratnine. 253 Hexamethylenctetraminc mandelatc. 253 Hexamethylmelamine. 429 Hexamethyl-p-rosaniline chloride. 227

llcxobarbital. ntetabolisnt of, 80, 94. 109 species differences in. 129 Hexylcaine hydrochloride. 6911 Hexylresorcinol, 222—223 Hib-CV vaccine, 214 Hibiclens. Set' Chlorhexidine glucunate High-ceiling diuretics. See Loop diuretics High-density lipoprotcins. 658—659 High-osmolar contrast agents. 473. 474t High-performance liquid chromatography (HPLC), 833 in combinatorial chemistry, 51,61 High-throughput screening. 26—27. 40. 40f, 43. 53—54, 541, 55, 61. 944. See also Combinatorial chemistry fultt'ntion assay in. 54. 54f

scintillation proximity assay in. 54. 541 terminology of. 60—63 Hipres. See Methenamine Itippurate Hirudin. 185 Hismanal. See' Astemizole

Hispril. See Diphenylpyraline hydrochloride Histadyl. See Methapynlette hydrochloride Histamine. 696-700 acctylation of. 122, 12M biosynthesis of. 696. 698f distribution of. 696—698 functions of. 700 ionization of. 696 life cycle of, 696—7(8) metabolism of. 699-700. 6991 release of. 698 stereochemistry of. 696. 6981 storage of. 6914

structure of. 696 tautomerizauion of. 696, 6971 Histamine H, antagonists. See Aatmhistarnines Histamine H, receptors. 698 Histamine H2 antagonists, 7(141. 7 18—722

structure—activity relationships for. 719—720.

7 l9f structure iii. 719—720, 7191 types of. 720—722 Histamine H2 receptors. 698—699 Histamine H, receptor antagonists. 727—729. 7281

Histamine H, receptors. 699. 727 Histamine H4 receptors. 699 Histamine receptors. 698-699 Histiocytes. 198 Histones. 833t, 835 HIV. See Human inimunodeficietucy virus

HMG-CoA tcductase inhibitors. 662-663.6621 Holo,tan. See lfosfamide Homatrocel. See Hotnatropinc hydrobromide Homatropine, 676—677. 6761 Homatropinc hydrobromide. 578 Homatropine methylbromide. 578

Honiology.based cloning. 167, 167t Homology ntodcling. 56 Hooke's law. 924 Hookwonn Infestations, 265 Hopkins-Cole test. 1434 l-lormone(sl. 840—1457.5cc ulw Steroid(s) antineoplastic. 433—438 gastrointestinal. 854—855 gonadotropic. 844—845 Itypothalatnic. 1140—84 I neurohypophyseal. 845—847 pancreatic. 847—854 pituitary. 841—844, 842t placental. 845

rDNA-derived. 861 recombinant. 175—177 thyroid. 1145 Hormone replacement therapy. 779. 787. 796—797, 796t, 7971

Hot pepper, 910 HPETES, 1120. 8221

HPMPC. See Cidofovir 5-HT,A agonists. 520 antagonists, 519—520

Humalog. See Insulin, recombinant Human anti-mouse nntibodies. 442 Human choriomainmotropin. 845 Human chononic gonadotropin (hCGI. 775. 845

Human deoxyribonuclease I. recombinant. 185— 186

Human Genome Project, 160 Human growth hormone, recombinant. 168. 175— 176

Human growth hormone receptor, cloning of. 172

Human itnniunodcfieiency virus. 3691, 372 Human immunodeficlency virus infection chemokine receptor binders for. 387 gp4l fusion activity inhibitors for. 387—388 HIV entry inhibitors (or. 387 HIV pnutea.se inhibitors for, 384—387 integrasc inhibitors For. 3811 newer agents for. 382—388

reverse trunscripaae inhibitors for. 372, 379—381

vaccine for. 382—383 Human immunodeficiency virus pmtease inhibitors. 384—387 des'elupment of. 942. 9431 Human placental lactogen (hPL), 845 Human plule.derived growth factor. recombinant. hO Human 1-cell leukemia virus (HTLV). 3694. 372

Human'uumor-colony—forming assay

(HTCFA), 394 Humate-P. See Antihemophilic factor. recombinant Humatin. Si-t. Paromomycin sulfate Humatrope. See Somutmpin for injection Humoral immunity, 200. 202—203 Hutnorsol. Set. Dcmecatjurn bromide Humulin. See Insulin, recombinant Hyaluronida.sc for injection. 838—839. 8394 Hybndoma techniques, 187—189. l81)f Hydnntoins. 504—505. 505m

metabolism of. 109 Hydralazine. 653—654. 6541 metabolism of, 122. 1231

vitamin B,, deficiency and. 893 Hydrazides. metabolism of. 122. 1231 Hydraeines. metabolism of. 122. 1231 Hydren. See Hydroxyureu Hydren. See Benzthiazide

974

irrtkx

Hydrocarbons. polvcyclic anrniatic. carcinogcnicity *1. 74. 741 Hydrochlorotht;izidc. 605—610, 606t. 6(1St. 620 Hydrocodonc. 733. 7331 Hydrircirdonc hitartrate. 746 Hydrvrcooisone. See alan (ilucocorlicoidlsl analogues o(. 81)6—11(19, 81)61

biological activities of. 806 biusyuthc'.is iii. 7691. 770, 804—805, 8041

deliciency of. 805 metabolism of. 805. 8051 prepanitiouts of. 81171—8081, 809t. SI!

relative activity of. 8(84 volubility of. 7701 Hydrocortisone acetate. solubility of. 770r Hydnucunisone esters. 8071 Hydrocorlisone NaN.)4 salt, volubility of. 7711t

llydrsuDltJRIL. See Hydrochlomthiazide llydrotlunuethnaiide. 605—611), 606t. 6081. 62)) Hydrogen bonds, 3(1—31, 31 t. 33—34

Hydromorpluone. 733. 733t. 745—746

Hydromos Set' Qainetharone Hydrophilicity. 31 Hydrophobic bonds, 3). 311, 831 Hydroiltiaeide diuretics. 605—6!)). 6061. 6061. 60%t

llydrou'. beurcoyl peroxide. 223 Hydroxocobalanuin. 894—896 l-lydroxyaiuphetamune. 537—538 acid. 22% Hydrvusvcarbamide. Set' Hydrouyurea Hydroxychloroquine. 2871, 28%. 295i 2—Hydnuxyestrogen. uretabuilisnu of. 12))

N-l-lydroxylamides glucuirunidation of. 114 sulloconjuigation of. 115 N-Hydroxyliitnines glncuronidalion ol. 114 sultoconjugalioti of. 115 Ilydrovylated anilines. 76(1—762 I 4-Hydroxyniorphone derivatives. 735 m-Hydriuxyphenol. 234 N-Hydroxyphenuernrine. nietabolisuti of, 91 Hydrosyprogesterone caproate. 786t, 7871. 788 8-Hydnixyquinnuline. 26), 471 Hydroxysuaurosporine. 439 Hyrlmxystilbamidine isethionule. 66% Hydroxystreptomycin. 337 Hydroxyturea. 42%, 43!

I lygroton. Set' Chlorthulidotie Hylorel See Guanadrel Hyoseine. 577 Hyoscine hydrobronride. 578 Flytiscyanrine. 574—575. 577 Hyoseyainine uu)fatc. 577

Flyperhiliruhincunia. neortalul. 115, 126 Hyperglycemia, in diabetes. 850, 85! lIvlut'rit'iinu pn'rjoraiitin (Saint John's svort). 908—9111

Hyperlipoproteinemia. 658—659, 659i in diabetes, 85(1—851

Hypersensitivity to aspirin. 82(1—821 to cephalosporuns. 325

to contract ugentu. 48! to local auue.stbclics. 689—690 tin penicillins. 31)8—3(19

Flyperstiut IV. Sen Dia,onide Hypertensin. See Angiotensin umide Hypertension. 642 —645 Hypeuihyroidism. 673 —674 Hyperv'ariable eegiruni. 188

Hypervitantinosis A. 870-871 Ilypcrvitaminosts I). 876—877

Hypnotics. See Anxiotytics, hypnotics, and

lutttnunohiotvigicals. 2(16—2)1'

sedatives Hypochlorxiuu acid. 223—224 Hypoglycemic agents. 668—673

limttrtuniuglohultuu s(. 202—21t6. 2(141. Set' also

higuanidines. 672 a-glucosidase inhibitors.. 672—673 nietuglinides. 67) sullonylureas. 668—67(1

Ihiazolindiones. 671—672 Hypoproihrontbinemia. cephalosporin-related. 325

Hypothalamic hormones, 840—841 Hysrerursalpingography. 480. 4801 Hytrin. See Terazosin

dcliniiion of, 21)6 examples of, 21(7 Antubuuslres

types 01. 2(14). 206. 2)161 lntmuniustiuttutants, anuineoplastic. 4411—44)

lutmunotherupy. for cancer. 440—442 lnmplunoit. Sit' Etitiurigesirel Improper torsion angle concept, 926 Ituturan. Sun' Azatltuoprumic

Inactivated polio vaccine, 21 tt, 21 lnamnnouc. 657 lndapamidc. 607—61(1. 18)71. (rO9t. 6211 lndcr.d. Sue l'nipr.iuuiihiul lndiuuavur, 385—387

1-131 —Metaiodobeneylguamdine sulfate. 469

Ibrirumoinab tiuxelan. 191 Ihuprofen. 758—759 metabolism of, 81—82 Ihutilide, 642 Idumycin. See Idaruhiein Idaruhicin. 4)5, 416, 423 ldeniity variables. 23 Idoxuridine. 375—376 as ptsrdmg

activalion of. 154, 1551 in chemical delivery. IS?

IItX. Set' Ilosfamide Ifosfanride. 4(81

activation of, 396 IgA. 206. 2061 IgO. 206 Igli, 21)6 lgG. 2(141. 21)6

1gM, 2041. 206 Ilopmst. 825 Iliusone. See lirythrontycin estolate Ilurtycin. See Erythromycin

Ilolycin (iluceptate. See Eiythromycin gluiceptule

Inuaging studies. radiiupharmaceuticals for. 454—484. Ste nifici Kadiopltarmaceuticals Imatlnih. 439. 44(1 Intciromuh pentelnre. 191 Inridazoles. structure—activity relationship for, 531 -532 Imiduzuuline receptor. 534 Imiglncerase. 186, 839, 8391. 859t. 861 Imipenern'cilastin. 317—318 Imipramine, 516—517 active metaholites of, 135r metabolism of. 771, 85. 87

Immune globulin. 207 Immune syslem cells of, (77. 1781, 197—2(81. 1981 self vs. nonsell in, (97 lmnuunity. 200—21)6 acquired (udaptivc). 2(81, 211111, 202—206, 21)6—216

developnient nil. 942. i)43) Indium

capriuntab pemudetide. 47(1

Indium chloride injeciuun, 47(1 Indium Oncoscunt ('RJOV. Set' lndiunr satumonrahpcnilctidc ursinc, 471 Indiunt pentemauc. 471 Indium Indium

pcuttreotide injection, 471

radiimpluarmaceuticals. 469-47) Indumutut satunriimahpcndctidr. 47(1 Induucin. Ste Induinuethacin lndomcuhacium. 754, 758 luidiumum (Hi luu

uuuciahsulisnu iuf, 98, 1119

Infergen Set' Interleron Inlultm—,itiiun anc.sthcsia, 687. Sn',' nil.sin Local anesm lieu ucs

lnflautmituatiott

ar,uchtidonic acid cascaihc in. 8)8, %l9L 82i)1 eucuisanoids in, 8)8—822. ,S'i'i' tiliti

Licosanoidis) Inflisimnab, 19(1

Influenza lype A, 372,373 Inlluenea vaccine, 21)9 Infrared spcctrosciipv. iiu csimbinati,riat chemistry. SI Inhulatiotual iunesmluctics, 486—487 Inhistiumm,Sr'e I'heniranuinc malcute lnitatc iumtmnnity. 2181—202. 2)Xti, 21)11, 2(12) Innovur.,Vee Fcuiuaimyl-droperidol

Inivsitol. 9fl()9tJ) Insecticides, drug imieuabolisnu and. 131 In siliciu (virmutal) screening .54 -55, 56. 63. 1)

Insulin. t76, 847—853 umiuio acid sequences in, 847. 84)6. 849 hiuusynlhesis ut, 847. 8481 huivine. I 7(u Iuulurc devs')impnucitLs fvir. 853

tnac)ivu)iiin iii. 849 lcnte, 851. 851i. 852t nteiaholic effects nut, 85(1—851

umietalnilusm of, Ill muumditicatiiuns nil, 849

porcine. l7rm preparatiiins nil. 851—853. 851t. 852t liroductisiut nil, 849

types of, 2116 unamneslic response in. 2115. 21151

uretiumuhinanl lunmuran, 168. 175—176.849.

reactions in. 205—206. 2051 celI-medinted. 21)2—203 cellular, 2(81

regular. 85!. 85 It. 8521

huimoml, 2181. 202—203

innate lnntuntl), 2(81—202. 2(8)1. 201t, 2021. 21)6

mucosal, 200 scrosal, 200 Immunizations

859t route ml udmuriuiusmr,ition um(, 852 853 secrmsuuimn nil, 849

species dillcrenccs itt. 847. 848t structure—activity- rclutiiumisliups fuir. 849

Insulin analogues, 849 Itusulitm infusinun devices, 853

Insulin unjectiimn. 85). SSlt Insulin punips. 853

definition of, 207

Insulin rcccplsur. 8511

schedule for. 212t, 215—216 vaccines for. See Vaccine(s)

Insulin ziiuc suspension. 85), 8511. 852u Intul. Su'i' ('ronrolyuu snidium

975

/nt/e.t

Integrilin Sri- liptilibatide Intercalated cell', ol itepliron. 6)8) lnterleriini vi, 179—IS)), 201 —202, 21) Ii. 2112t alpha. (79 — ISO. 17% I SOt, 201 -21(2. 202t

antiviral activity ii). 373—375. 3741 3751 antineoplastic activity ol. 441 antiviral acus ity of, 373— 375.3741. 375) beta, 179— ISO, I 7th 201 —2(42. 21)2t

anliviral activity iii, 373—375. 3741. 3751 classification iii. 17')— 18(1, 179t, t8(It functions 0). 1771. 179, 21)1—2)12. 21)31 gamma. 179—180. 17th. 2(11 --2(42, 202t

a'ci'nthinant. 180-182, (SOt. ISli, 85th. 81411, 861 —862

antineoplastic actis ity ot. 44) anthtml activity ii). 373— 375. 374) Intc'rfrron aIIa-2a. (8)). 181(1. 861. 869t

anlineoplastic activity iii. 44) lnterleriin alfa-2h, 1811-181, 1811), 859t. 86 1—862

.intineiiplastic activity itt, 441 Interlerrin alt'acon- I. I SOt. 181 Interferon alla-it I. (Slit. IS) litierferon aIIa-n3. l8()i, 181. 85th, 862 attliticoplastic activtlv of, 44) Interferon beta- I a, (SI — 182. 1811

lttterleron beta- lb. lsIt. 182. 8591, 862 Interferon gaiuuiia- lb. 1811. (82, 859t lnterleakitts, reciinibinani, 182—183. 44) --442, 859t

lnterntediate-density lipuproteins. 658—659 Intenin Sit' litterferon alfa-2b Intetstitial cell——sliuttulating (tiirutotte. Sec l—uteirtietrtg hurntinte I_Il,

Intestinal dnig ntetabolistri. (.6, 67 Intestinal eneymes. 4 Intestines, Si-c aLit,

Gastriiiuttestinal

drug ilelivery to. 158 Intiwosirin See ('attire Intramuscular injection. dnig distribution anil. 41. 5 -6

Intrauterine device. progesterone. 793t. 794

Intravenous adittinistratiou. drug ilistr.hiittiui in, 41. 5 lntnivenous anesthesia general. 487—488

regional. 687, Sit' alsii Local anesthetics Intravenous itnniiitie globulin. 2(17 Intravenous pyeliigrnpby. 478. 4781 litlravenous regional anesiltesia, 687 Intravenous urography. 478 Intrinsic lactur, 895 Intron Inter(eriin alfa'2h Inlrons. 162 Inverse agottisls. 485 Inversine. Sec l'rittielhaphan cainsylate Invirase, Sec Saquinavir 586. 679 Involuntary nervous system. lobeuguane sullate injectiou. 469 Iobitnii(iil. 482 locetamie acid. 482. 482) Iodine. 223 Iodine rudiophurntaecuticals. 4(i)) —469 lodipamide tneglutrtine, 482—483

Iiidinanol. 483 Iiidopliors. 223 Iiidixpiinol. 261 Iodntopz. Sec Sodiuiit iodide I 131 lohevol, 482 Iimattiin. Sri- Phencermine iott-escharige resin Ion channels, 553, 681

Iveruiectin. 268 Iviitiiec. S,'i' Iverinectiiu

681 —683. (.82)

piitassrtint leak, 681

seleciisiiy of. 684-685 sodium. 681. 682—683, 6821 truusmitter'gated. 683—685 viiltage.gated. 681

Iou-dipole bonds, 3Ii Ion encliange chromatography. 834 Ionic bonds. 3(1, 311-Sit' u/in Hotid.s Ionic ratio P.S contrast agettls. 473, 4741 Ionic ratii, 3 cirutrast agents. 47) loniciug radiation. 454. 457 lim Ir.utspon. 681—683. 682t lopanudol. 483 lopanoic acid. 483 Iiipidiiie .Sei' Apraclonidine loprotuide. 483

bind. 483 loversol, 483 lievaglale. 483 lovilan, 483 Ipratropimtr hri'iuide. 578— 579 Irbesartan. 649 Irinotecan. 426 Iron, in hemoglobin. 83$ Ischentic bean disease, 622-623. 6231 Ismelin sultate, 5cc Cuanei(iiditie niimosullate lstiactinotuycius. 415 Isobars. 455 Isohfeiimycin

Ketliui..Si-,- ('ep(ialiclhiui

Ketitnil. Sit- ('epltalestn Ket,i,( Set' ('eiaei,Iai Keatardniu .S.'i' Priicyclidine hydrochloride Keratolytics. 222 Kerlitite. Si-i' Hetaviilol Kcrnicienis, neonatal, 115. 126 Ketalar. 5cc Ketainine Ket.attitie, 488

titetabulisiti ol, $9 Keiiibeimndonie. 73ht

Keiocona,.iile, 212- 243 Ketone carhony Is, ntietalx,Iisuti ol, 11(1—11(7, (12— 113

Kcmimes, metabolism ot , 'N III) - (32— 13,1

Keitipritien. 75i) Ketivolac trotiiethaniine, 759—7611

Isoetharine. 537 Isolliiiirplnaie. 51.1)

Kiditey Ncr itfiti Netthntn

Isiinieric traiisition. 455 456 Psi titter' i-i.,. 31—32

Kliaiopin .5-c Koate III'. Sic Antil.cmophilic ('actor.

£32,321

recoitthtnanl

geometric, 32 4-36. 35. 371

KiSdIiNate.Si c Antilietitoptiilic faclor, recivttbniani Kogenatc.Si-i-Antihentophilic lactor. cecoinlvicint

5, 35 -36.371 maci. 3 1—32

iii acetylcliiiline. 34—35 7, 32. 321 Isottiethailone. 738, 7,(9t

Kt yofinie, 71, It. 762 $1' 61-19. 42tt

Knpller cells.

Isoniacid. 254— 255

interaction of with 124 metabolism it. 122. 1231. (24 vitamin II,, deOciency anil. 893 Isoutcotintc acid ltyibr.ieidc. Si-i- Istiniacid Isitnicotinyl hyilracide. Sc-c Isinmiaeid Isopcntaquine. 288-289, 2891

tunic Isophane insulin suspeuisiin, 8511. 852. 852i Lsiipm)vnniile iodide. 584—985 Isopropanol. 2211

lsiipnipyl alcohol, 220 Isopruterenol. 536 nmeiabolisui of, (25, I 26

IsoptinSi'i' Verapainit Isurdil..S'm'c Isosorhide ilinitr.ite, dilinied Isitsorbide. meiabolism itt, 12(1 (sosiirhide dinitrate. itiliitcd, 625m. 627 Isosreres. 4(1—41, 4It 342. 3431, 3-13 Isottipes. 455

Isotrelitloin. 873 Isradipine. 631

calcium. 628. 6281

Iterative deciinvolution. in combinatorial chemisury. 50

solute reabsiirputiin inSiIh.__64l I. 5i)7) -

saltienamide tnjtiry of. 122, 274 Kidney failure, drug uiielabiiliies in. (34 Kinins, in blivvl pressine regulation. 6—14—645

iii acetylcholiue. 34-35 cuiiforinatioual.32—- 33

ltracona,ole. 243 24-I

Ketotilen lnmar,ite oplalt.ilutuc solution, 717 drug escretiivt via, 41. 5

Isolluraiie. 486

Isuprel. See lsiipnoterentol

681

Kallidiu. 851. 857 Kalhkreins. 144, 557 Kanamycin sulfate. 139 aittitubercalitus actis its ii). 254.339 iicictisatvvi ol - 116, ill.) Kantres Sri- Kanatttycin snllate Kellev, Si-i' Cephalesin

Isodine Sit' Pin idiine-iiidiiie

acetylcltiiline and. 548—55(1

ueurotrausntutters .ini), 683—684. 684

K Kabikiutase. Si'i' Sirepti'kitiase KaI,i-a,ar. 264)

Ks.

I

(.inilauie

Kss iIiI,iite. Sc,' l.utd,nie

IAAM, 73$, 739t. 7-19 I .atueling mdcv. .1') I

I ,,ibetiulol. 54), 5461 /d-I mctani uitibn,tics_ .1(11

-

31-I, .1111 —33.1

ii!',' ,-\itt,hiotit-s: ('cplialitspmniius:

('enicilliittst itoiihle-estcr loon ol, 146 (37, 1481 /'si'ui/tilvii;uit resistance tim, 325 sirncture itt, .1) 12i - 3113t

$'Lactamti.ise niltibitors. 5(4 118 carhapenenis as, 3 If,— 3(5 cephaliis1v.tins ms. 323- 325. 324), 326i

class 1,315 -ll(i classiticattivi '.1, 115

class II, 1(5 ilotihlc-ester lorm of, 146 147. 14Sf insestigaitintal. 3)8 nttecliattisni ill actomti .if_ 3(5,3131 pcnicillin.ise resistance .1,124 siructure of, 3151

sasccptilvlils ii,. 3(5—3 to types uI, 314.— 118

.'m'i'i'

976

Inde'r

acuitnases. 306 cephalosporin susceptibility to. 324 elussiftcauon of. 315—316 inactivation of. 315—316 by ccphalosporins. 323—325. 3241. 3261 rcsislance to. 309. 3091, 326t Lactoferrin. 201 Lactoflasin. 891

ltctylphenelidin. 7611. 762 Lamiclal. See Lamoirigine Lamisil. Set' Terbinafine hydrochloride Lamivudine, 381 Lumolrigine. 507 Lamprene. See Clofazimine l..attgerhans cells. 198. 199t Lanusterol t4a.demelhylase, 240. Lanoxin. See Digoxin Lansoprazole. 722. 7231. 724—725 Large intestine, drug delivery to. 58 Lariam, See Mefioquine hydrochloride Larotid. See /smoxicillin

Laser optical encoding. 53 Lasix. See Furosemide Lasofoxifette, 78 If. 782 Latanoprost. 828 LCAO method, 937 Lead compounds, 59—60. 591. 61—62 Lecithin, 901

Lee and Richard surface. 922 Leishmaniasis, 260 l..ennard-Jones. potential, 926 Lentaron. See Fonne.stane Lerne insulin. 851. 85 It, 8521 Lepirudin, recombinant. 11(5 Leprosy, 279—280 Leritine. Set' Anileridine

Lescol. See Fluvastatin Letrozole, 435. 438, 784. 7841. 785 Letter. See Lcvotliymxine sodium Lettcine..enkcpltalin, 744, 843 Leucovorin, 410 Leucovonn calcium, 807—898 Leu.cnkephalin, 679. 744. 843 Lcukeran. See Chlontrnbucil Leukenn. See Mercaptopurine Leukine. See Sargrwnostim Lcukotrienes. See also Eicosanoid(s) biological activity of. 822t biosynthesis of. 8201 Leuprolide, 437 with untiandrogen.s, HIll as antineoplastic. 435 Leurocnstinc. See Vincrisljne sulfate Leustutin. See Cladribine Levalbuterol. 537 Levallorphan. 739. 740 Levalloephan tarlrate, 751. 7521 Levamisole. 441

Levanone. 7391 Levutol. See Penbutolol Levobunolol, 543. 5441 Levodopa. metabolism of. 125 Levo-Dromorun. See Lcvorphanol tastrate Levoid. See Levothyronine sodium Levomethadyl acetate hydrochloride. 749 Levonorgestrel. 7861, 7871. 789 in contraceptives. 79lt—793t. 794 Lcvonorgestrel-releasing inleaulerine system. 793t, 794

Levuphenacylmorphan. 740

Levoproine. See Methotrimeprazine Levomsine. See Levothyroxine sodium Levorphanol tartrate. 739. 740. 750

1_evothyroxitte sodiutu. 673 Lcvsin sulfate. St't' Hyoscyatninc sullate Lewis structures, 935 LH. 774—775, 7741 Libraries, combinatorial. 26—27, 43. 441, 55—58, 62. St't' also Combinatorial chemistry Librium. See Chlootiasepoxide hydrochloride Licorice. 916—917 Lidocnine hydmchlonde. 639. 6391. 67(1

ftrst.pass effect and, 7 half'life of. 7 metabolism of, 85. 109 Ligation, in cloning. 165 Lignocaine. 678. 69(1—693, 692t metabolism of, 686. 6861 Lincocin. Set' Lincomycin Lincoinycin. 353—354 mechanism of action of. JOttt

Lindane, 261)

Linear chain molecules, combinatorial synlltesis of. 45—46 Linezolid. 363 Linkers, 48—49. 41(1. 62 Linoleamide. us sleep-promoting agent. 4118

Liothyronine sodium, 673 Lipid(s) classes of. 657—658 metabolism of. 657—658 suucture of, 657, 6571 Lipid-lowering agettls. 659—663 HMO-CoA reductasc inhibitors, 662-663 Lipid membrane bilnyer structure 19, 91 chemical nature of, l9 chmmtesterol in. 231, 2321

drug movement across. 19

drug panitioning and. 19—21. 191 ergosterol in. 231. 2321 n.octanol/watcr syslem model of. 19—21) panitionirig phenomena and, l8—2l. 191 properties of. 19 receptor component?. of, 2$. See al.r,i Receptor(s) Lipid metabolism, insulin clfects Un. 850—851 Lipid solubility. 5 pK,,and. 16—17 Lipid-soluble vitamins. 866—8115. See also Vitamin(s)

Lipinski Rule of Five. 40. 55. 62 Lipitor. See Atorvastatin Lipophilicity. 31.65 Lipoprotcins classes oF, 657—658 metabolism of, 657—658

structure of. 657, 6571 Lipotnipins, 843—844 Liquefied phenol. 221 Lisinopril. 645—646 Lisler. Joseph, 217. 221

Lithanc. See Lithium carbonate Lithium carbonate. 503 Lithium citrate. 503 Liver, drug metabolism in. 7—8. 66—68 LKTs. 820, 822 Local anesthetics. 676-694 alkaloids. 690 690—693. 6921, 692t

aniline derivatives. 690, 691.. 6921, 692, benroic acid derivatives. 690, 6911, 692f. 692t. 6931 buildup of. 687 cardiovascular effects of. 689 central nervous system effects of. 6119 classification of, 690

definition of. 676 discovery and development of, 676—67 duration of, 688—689 eIfcctis'eness of, 687—61(11

elintination oL 61(7 in epidurttl anesthesia. 687

ester-based. 690-693, 6911. 6921, 6931 in field block a,testhcsia. 687 fluid pH attd. 6118 general, physiology of. 485—486 hydrophilie center of. 692—693 hypersensitivity to. 689—691) with hypotltemmic action. 690 in infiltration anesthesia, 687 in intravenous anesthesia, 687 lipophilic center of. 690—692, 693 mechunism of action of, 684—687. 6851 metabolism of. 685—686, 6851 methetnoglobinemia and, 689 miscellaneous. 693, 694t neuronal stimulation and. 688 neumnal susceptibility to. 687—688 partition coefficients oL 693 values of, 693 protein binding of. 693. 6931 rate of onset of, 688-689 in regional nerve blocks. 687 mutes of administration for, 687 side effect.s of, 689—691)

site of a-lion of, 685. 68Sf solubility of. 692—693 spinal. 687

slnicturc—activity relationships for. 690 6921

topical. 687 types of, 690-694 vasoconstrictors with. 61(8 wound healing and. 68') Lodine. See Etodolac l,odoxarnide trotnetltatttitte. 716 L,,fetttiinil, 738. 8371 Log 0 values, 948t—956t Logen. See Diphenoxylate Log P values. 9481—9561

Lollypops. in combinatorial synthesis. .14. Lomanate. See Dipltenoxylate Lomeflonucin, 248, 248t. 251—252 Lomotil. Sit' Diphenonylate Lomustine, 399. 401—402 Loniten. Set' Minoxidil Lonox. Set' Diphenoxylute Loop diuretics, 6 10—616. Set' ,,lao Diureti miscellaneous, 615—616 organotncrcurials, 610 phenoxyacct,c acids. 6l3—6l5 preparations of, 62)) 5.sulfamoyl.2./-3.aminobenzoic acid derivatives, 610—613 Loperantide. 737. 7371, 748 Lopid. See Gemlibroril Lopressor. See Metoprolol Loprox. Ste Ciclopirox olan,ine Lorahid. See L,,racarbef Loracarbel. 320t, 3261. 327 Loratidine. 713—714

Lorazepam. 491 Sec Probucol Lorfan. Si',' Levallorpltaut turtrale Lorothidol See llilhionusl Losatlan, 6411 Losec, See Omcprtuole Lotemax. See Loteprednol eiab,unate Lotensin. See Benaeepril hydrochloride Loteprednol etabonate. 8111—811. 8111, 812—8 13

hides

I,otrimtn.S,'e Lovastatin. 662

Low-density lipoprotcins. 658 —65') Low-osmolar contrast agetits. 473 l.oxapinc succinute. SIX) Loxitane See Antosaptnc locoL See Indapaitside 1.51). .20. 521

Ludinmil Se.' Maprntiliite hydrochkiride Lugrils solution. 223 Lumigan. See Biniatoprost l.untinal.S,'c Plie,ioharbilal Luncllr, 792t. 793—7')-l Lupron. See Leuprolidc l.upus syndtounc. acetylation pol)morphism and. 124 Lutalyse. See l)inoprnsl trimeihauiiine Lutcinliing hormone 11.11 I, 774—775. 7741.

laser ilcsorpttiiit/ MALDI—TOF ) iottiiulioit tiltie—ot- tlighL I, 52 Malorone. See Atovaquone.proguainl rn-A MSA.See Amsacrine Maitdelatitiitc ,' Methenatnine mandclaie Mandi.l. See Celi.ntundote nafiae Mangakolipir tn'.s.diuttt. 477

Menthratie(s)

chemical tiature ii).

drug uitosctticnt across. I') drug partitioning attd. 9—2). 191 luyperpolari,,ilt.iui i.l. 4,8)). lull II iii. trautsp.url across. 1,81—68.1, fi$2(

Manganese conspiexes. as contrast agents. 477 Mania. 503

Manic disorders. 496

lipid hi)aycr i*I, I'). 191 ,:—octaitohls'.atcr svMeutt model of,

Mannicli base, 149. 15(11

Mannisidosireptiimyciti. 337 Manoitol. 618. 4.20

Maiisonil S.c Niclosatitide

rcpiularicaliiilu iii. 1,8)), 1,8)1

MAOIs. 514—516. 51St Maolate .', (liksrphencsiit carhaitiate

Maprnliline hydrochloride. 5)8 Marcain ic Itupis'acainc

puuteitti.il. 611(1—lull). 1,81)

Memiury respisnsc. in ituuututiuiity. 21)5. 21151 sodi,tni diplitusphate. 1185 lSIeit,udiiiite. 885

1.ymphocyies 8, 200. 202—21)3 T. 200. 202—203

Mauicaria ,l,antom,lla (chamomile I. 911

Met,iuigoc,iccal pithy Mcnitgarih. 417

Statrit.a.sststed laser dcsorptiouiltoniiation

Mcutiitropins. 1)44—K-IS

5 1—52

M

M it't'pti.rs. 55) mc piors. 551 M, receptors. 552 Ma rei,eptors. 552 M, receptors, 552 Macrodautin. See Nitrssfurantoin Muerolide antibiotics, 349-355 cheuni'.ry of. 349 rucehanisni iii neinin nI. 349 to. 349 microbial

as priidrug. 4—5 Menadiotie siu,titurn Mcnaquinuiuues. 882

885

Menesl. S,.' Eatrogcns

Mas) cells, 198 Mast cell stahiliorrs. 715—717

uirne—*sI—lliglut MA) .DI_1OIi), 52

Mains Gla protein, 883—884 Matris tiietallagrotca.scs, untineoplastir.

Lypre.ssin. 1)47

acid dielhylainidc. 52)). 521 Lvsodren.S,'e Milolane Lysocyme. 20)

a ,iccine, 215

Menstrual cycle, regulation at. 774—775. 7741 Meat/ia /iuk'eiiiiii (pcnityroyal I, '115 Mcpcit,olate brisiutide. .98 I Mcpcridune. 735- 738. 747

Mritulane S.'.' I'rocarbaeine Itydniclikiride

discovery ill, 735

Mavik Set' 'l'randolapril Masair.S,'e Pirfutiterol Musaquiit.S,'i' Loiutelloxacin Maxiputtte.Se.' Celepime M,itside.Se,' 'l'riaiiutercne-hydrsuchluinilhiacitle Mcaslc'.'inuiiips.rubclla iMMR saccine, 211.

iiieta)xulisuu, of, 85 87 tti,udilicatt,utis of. 735 731), 731,1-7310 stntcture iii, 731'it

Measle.s sacciute. 216—211. 2121 Mebcoda,.ulc, 265—2)16

Mcphcncsiru, 4'))1

Mephcuiytoiiu,5)tS, 5))Si

Mi.pliuiharbilal. 494 494t actuse utetabolites iii. I 35t a'. aiiiiconsiulsant. 504 as atistiilyuic/.sedative-Ius politic. 494. 494t

Mcc.uunylamine hvdnucliloride. 588—589

Mechlorethamltte hydrochloride, 399—Ill)) Meclat,. Set Meclocycline sultosalicylauc Medicine Itydrocltboride. 7)17 Mcc)ocycline sullosalicylale. 3451, 347

nictabolism of. 94 Mephyton. St-c I'll> tonadionc Mepi'.iicaiutc, 1,78. 1.9)) 1,93. tu')2t

.l')i meiaholisuui iui, 82

Mcclolenaunute sodium, 757—751) Mecl,uisicn.S,',' Meclistenauutatc sodium

Mepr.uui. S,'. Alovaquonc Meprylcainc

Nlcpyrautuune. Ste Pvril&ttitiuue tualeate

Malenide acetate. 278. Ser' also Sulfonamides

Mrda,epattt, tneualxulism of. Ill I Medesa.S,',' Valruhicitu Isledical imaging. rathopluaniuacetiticals tar,

indications br, 270t Magan. See Magnesium salicylate Magic angle upinning nuclear tnagnrtk'

Radiopliartuarenllcals Medicinal chieutistry. oversiess of.

spedraim of activity o(.349 types of, 349—355 Macrophages. 198—2(1)). 199t, 204 Mitcula densu cclls. 5971. 5')9

resonance spectruscopy. SI Magnesium salicylate. 755 Magnetic resonancc imagtng. conirast agents for, 475—477, 4831. 484. Se.' alto

Contrast agents Magnevisi. See Gadlipenletitte dititegluntine Ma huang. '105. 911—912

Major histocontpatihility comples IMHCt. 197. 199—200

Major tranqttiliiers. 496—503 Malaria ilrug-resistaztt. 21)2. 289-290 drug Ilterupy 11w. 283. 2'J5—298. See a1si.

Antimalarial'. geographic distribution of. 282 itflJstct iii, 282 mosquito control (or. 282—283 nutrittonal sttppon in, 285 pathophysinlogy of, 283—285. 2841 Plaamudii,n, spp and. 282, 283— 284. 2841 protective ittlitatiolts br. 283 vuccine.s for, 283. 283. 285 Malathion. 570. 5701

I t)2l)

pltenoitiena atiil. 18—21. 191 propcntes 0). 19 receptor components a). 28.5,-,- also

Marecine. Si-c Cyclicune hydrsuchlondc Ma'.'. spectmtttctrv. in counbinatorial chemistry.

tumor.iitliltraling. 442

1)

depolaricatisun ii). 1,1(1), (.811. 1,1)2

84). 844 Luteinicing h rut inc—releasing honnone. 1)4 l.uvox. See Hiwonaminc LY 303366. 246 LYMEnu. 11)6

l.ymphoid cells. 97, 1981. 218)

977

454—484. Sri' is/a,, I —2

Mcalroxyprssgesterone acetate. 7861. 7871, 788 as antiuteoplastic, 434

its contruceptive. 792). 793 in hnrntiuuie rcplacenictit ther.tpy. 7i16_71)7, 796i

Medrysone. 81)1,8111.813 Mefenamic acid. 757 Melliuqttine hydrochloride. 2871. 288. 2951 Melosin. Sc'i' Celoxiti,, sodium Metnuside. (8)7—6)1), 1,071 (iOçt. (i2lt

Mcguce. Sri' Megcstn.l acetate Megesurol acetate. 436. 787). 788 as atitittetuplastic. '134 Melattiicyue.stimulatittg liiurnt,.ne. 8.13—1144 Mclunocytc-stintiulating honitisute release-

6')0 693. 691t

Mers-aleukinSe.' (s-Mercaptnponne 6-Mcrcapuupiiriuuc. 411—412 itiecliautisiu of action nI. 4(14 — 4)15 tuiciabsulistit ii), 3$. 99, I 2)t, 126. 4)1-I —41)5 Mercapluruc acid diuiujugatioui. 117—121

Mercuric ,iaiik, 221) Mercury cornpiuunds. 228 diuretic, 6111

MrridiaS,'.' Sihutraniiiie \ler,upenent. 311) Mer,u,i,ites, /'/asuuuoduui.,, 2114

43 44f 481 Merltuiolatc. Sc.' Iltinucrosal hk_salaunitue. encytutitic degriid.ititsn ii). 3—.) \lesantoiui. See Mcphenyttuiut Mescaline. 521 uneiabalisnt 01. '31. 9)), 122. 1231 Mesuia. 4-45. 446

Mesnes Se.' Mesna Mesopin. 5cr

niciliylhru,tnidc

inhibiting tactor. $41 Me)autotropitt'.. 843-844 Melarsoprol. 263 Melatoniti. as sleep.proitioting agent. 488 Mel 115(1' Melarsoprol Mellari). Sc.' Tltinrida,.inc

talesiirida,iuue

Mehosicatn, 76)) Melphalan. 4(10

Melah,ulic aruuunati,ation. 101

ii'. ,ieuiae ntetal*olite. 135. l3St metahislisnu iii, 99 Mesoridar,,ie hes) late, 499). 5)1)) Messenger RNA. 162 Mestrutiiul. in nuoitopltasic ciitttniccpiives, 71)11 Mrtabolisuii. See I)rug tiucuabolisnt

978

Index

Metubolites achy zfte. 7—8

tOXiCity of. 65 Metaglinides. 671 Mctuhvdnn. See Trichlurtoethiozide 3 - Metaiodobenzvlguaitidinc sullate. 489 Metaphen See Nitromersol Mclapmtcreno(, 536 Meraraminol. 539 Metastron. Set' Strontium 119 chloride Met-enkephalin. 679. 744. 1(43—844

Mctlonnin, 672 Meihacholine, 557—558 conformations oF. 555—556, 5551 Mcthacholine chloride. 558—559

Methacycline hydrochlondc. 345t. 347 ol—).Methado(, bts-N.demethylated nietabolde of. ucetylation of. 122, 1231 Methadone. 738, 7391. 749 metaholisiti of, 85, 111Sf structure—activity relationships of. 738 Methamphctamine. 513 nictitholisut of. 89 Methampyrime. 7621. 763 Methundroslenolone, 7991, 801 Methanthclinc bromide. 581 Methapyrilene hydrochloride. 705 Metharbital, See Mephobarhital Methaiolamide. 6041', 605. 6(9 Methdilarinc, 711 Mcthdilaiinc hydrochloride. 711 Methcinoglobinemia. 93 Melhenuinine, 253 asprodrug, 151—152, 1511 in drug delivery. (56 Methenamine hippurate. 253 Methenamine ittandelate, 253 Methicillin sodium, 309t. 31(1. See iris.. Penicillin(s) Methimacole. 674 metabolism of. 114 Methionine. 901 Methionine-enkephalin. 679. 744. 843—844 Methocarbumol, 496 Methohexitul sodium. 487. 4871 Meiholrexute. 41)9. 414 leucosonn rescue with. 4111 structure of. 9421 thymidinc rescue wilh. 410 Methotrimeprazine. 751 Methoxamine. 533 Methoxytlur.me. 486 Meth,suxitnide, 5(16

Methyclothiazide. 605—610, 6061. 608t. 620 N.Methyl-4.aminoarohenzcne, tretdatum of, 93 Methylation. in drup metabolism, 125—126. (261

Methylbcn,.ethonium chloride. 225 3-Mclhytcholanihrone. metobolisni ol'. 771 Melhylcobalunhiti. 895 Meihyldihydroinorphinone. 733t Methyldiphenhydramine. 71)2 Methyldopa, 535. 5351 metabolism of, 92, 125 Methyldopale, 535, 5351. 652 Methyknc blue. 227—228 Meiltylglyoxul his(guauylhydrazone). 429 Methylhydrazine. 397

relative activity of. 8091

Minipres.'.. Set' Prazosin

sotuhilily of. 5

Mittocin, Set' Minocycline hydrochloride Minocyclinc hydrochloride. 3451. 348 Minoxidil. 654, 655 metabolism of. 84 Miiitezol. See Thiabcndaiasle Miradon. See Anisindionc Mirena. See l..evonorgesttet-releasing intr,iuterine system Mirtazitpinr. 520.541 Misoprostol. 126. 827—828

Methylprednisolone sodium succittate

solubility of, 5 sU'uctuuv of. 77(1 Methylrosaniline chloride. 227 Methyl solicylute. 754 l7o-Mcthyltcstosterone, 798. 7991. 801 biological activity ol'. 798. 7981 hepatolovicity of. 798 structure—activIty relationships for. 798—799. 79t)t

structure of. 77(1. 799f Methyl-ThFA trap hypothesis. 895 Methyliraitslentacs. 125 Methyl violet. 227 Methylsunthunes. 5(0. 511—512.51 Ii Metiaiuide. metabolism of. 99. 11)1 Mctipraiiolol. 543 Metucunne iodide, 591 Mctnln,onc. 61)7—610. 6071. (419t. 620

Metoprolol. 544. 545.5451 active metabolites 1351 nsctabolistti of. 77. 98 Metnwole. Sr.' Pentylenetctra,ote Metrilonate, 567 Metneamide. 483—484

Metro IV. See Metronidacole Metrottida,.ole, 260—261 metabolism of. 1(17

Metyrupone. metabolistit of. 1051 Metyrosine. 528 Mevacor. See I,.ovastatin Mevristutin. 662 Menilctine hydrochloride. 641) Mexitil. Set' Mexiletine hydrochloride MeLOn. See Me,.locillin sodium Meulocilliti. See also Penicillin(s) spectrum 0) aclisity of. 308

Meelorillin sodium. 309*. 3(4 Mibcfr.tdiI. 945 Micurdis. See Telmisariun Micatin. See Miconaeole nitrate Michael addition reactions. (20 Miconazole nitrate. 242 Microbial resistance. 31)1. 3(15—307. 335—336

Microchip spatial arrays, in combinatorial synthesis. 44. 451. 60 Micronasc. See ('ilyburide Microride, Ste Hydrochlornthiaeide Midamor. Set' Amiloridc hydrochloride Mudazolam. a'. anesthetic, 487 Midodrine. 533 Mifepnstone. 795, 7951 Mifiprex. See Mifepristone Miglitol. 672—4.73 MIH. See Procarba,ine hydrochloride

MMFF94 Force Field. 925—926

MMR vaccine. 211. 212t MNDO method. 938 Moban. Sit' Mohindone hydrochloride Mohic. See Meloxicam Mobidin. See Magnesium saticylate

Modafinil. 5(0 Moduretic. See Atniloride.hydrochlonithia,ide Molar reactivity (MR). 21. 2lu Molecular connectivity, 24. 24t Molecultir diversity, quantification of. 56—58 Molecular dynamics sitttuluiions. 933—935 Molecular mechanics, 3(1 Molecular nixxleling hull-and-spring models in. 923—929. See .also Force field iiiethods computer-assisted. 27—41, 919—922,9211, 9221. See ii!..., ('ompstier-assisted drug design ('PlC models in. 920. 921—922

physical. 920 solvent-accessible surfaces in. 922 van der Waals surface in. 922. 9221 Molecular orbital calculations, 935 Molecular similarity, quantification of. 56. 57t Molecular structure drug—receptor interactions and. 31—34 physiologic activity and. 11—21. 28. 31—41

Molindone hydrochloride. 502 Molyhdenum.99. production trl. 462. 462f,

Miltown. See Meprobam-ate

Monoacylureas. 51)6

MINIX) method. 938 Mineraloconicoid(s). See also Steroid(s) biological activities of, 81(5

Monoamine oxidase inhibitors (MAOIs). 5(4—5(6. 51St Monoamine i)tidaccs (MAlls). 90—91.

exccs.s of, $05

modifications of, 806—807. 806t products. 8071, 810—811

relative activity of, 809. 809t structur.il classes at'. 8(16—809 struchitre—activity relationships, for. 807—808.

Meiliylprednisolone. 8(11(1

Mitrobronliol. 395 Mivacron. See Mivacanum chlonde Mivacurium chloride, 593 Mixture library. 43. 441 MM2 force field. 927 MM3 force field. 925—926. 927 MM4 force field. 925 —926

Moinetasonc t'uroatc. 8(3. 814, 8141 Monisiat, See Miconucole nitrate

N.Methylmorphinan. 738—739. 742 Mctltylnitrnsurea. 395. 398

Mcthylplienidate. 514 netabolisun uI. 89. 1(11. 11(9

Mltoguazone. 429 Mitomycin C. lIMIt, 4(4. 423—424 activation of. 152—153. 1531. 397. 397f Mitomycins. 419—420 Milusis. 391. 3911 Mitoiane. 436 as tintincoplastic, 435 Mitoxantrone hydrochloride. 429. 432

914 Mtlk Millon's test, 834 Miloittm. See Pliensunlittide Milrin.me. (.57

Methyl ioidide. toxicity of. I (K—I 19

Methylparaben, 228 —229

Mithrurin.Si'.' Plicamycin Mithrainycin. See Plicamycin

11071—%08f. 8091

structure of. $071 Miner.iloconicoid receptor antagonists. 1115 Mineralocorticoid receptors, 773

4631

526—527. 5261

Mon,.umine reuptake inhibitors. 5(6 Monobavtaiits. 334 Monocid. See Cefonicid sodium Monoclatc-P.Sr'e Antihemophilic factor Monoclotiat antibodies, 181—191 as untineoplastics. 442—444

chiuneric. (89 diagnostic. 471)

preparation of. 187

Fader in rudionuclide lest kits, 190—191 therapeutic, 191 types ol, 119—191 Monocytes. 198—199. 1991

Mononine. See Factor IX. recombinant Monoprit. See Fosinopril sodium Moricirine, 1,40 Morphine and related compounds. 731 —753 addictive liability of. 732. 733. 744 discovery isl, 744 historical perspective on. 733 indications for, 744 metabolism of. 85—86. 86. 87. 98. 112. 126 modifications of based on Grcwc's research, 738—741 based on Isleb and Schat,mnnn's research. 735—738

based on Small and Eddy's research. 733—735

early. 733—74 I

pharntacologic properties of. 744 preparations of. 744—745 products. 744—751 receptor i,twraction.s with. 74 1—743. 7421. 743?.

solubility of. 744 source of. 744 struclure—uctivity relationships (or. 733—735, 734t—735t. 741—744

synthetic derivatives of. 733 Morphine hydrochloride. 744—745 Morphine sulfate. 745 Morse curve. 925. 9251' Mosquito control, for malaria, 282—283

Motilin. 855 Mottr tterves. 548 Motor tteuron, 680 Mottin. See Ihuprofen !sloxalactajn, 325 mRNA. 162 Mucosal immunity. 200 Mucus. 200 Mulliken population analysis. 939 Multillance. See Gadobenate meglumine Multiple sckrosis. 181—182 Mumps vaccine. 211, 2l2t Munurol. See Fosfomycin tromethaminc Mupirocin. 362—363 Muromonab-CD3. 190, 859t Muscarine

activity ol, 556 isomers ol, 556, 5561' structure of, 5581' Muscarinic antagonists. 558—572, 559f Muscarinic receptors, 5511—553, 55 If, 5521 ucelylcltoline and. 557—558, 557f, 557t structure of. 557—558. 5571. 557, subtypes of. 551—552 Mustargen. See Mechlorethamine hydrochloride

Mutamycin. See Mitomycin C Muzolimine, (ils—616, 6151 Myantbutol. See Mycelex. See Clotrima,ole Mycifradin. See Neomycin sulfate Mye'ohas':erium avium, 254 Alveobacterium insracellularc. 254 Mvcobactc'riun, Lansa.rii. 254 Mycabacterrurn leprac. 254. 279—281) Mycabacrr'riunr rubercu!osi.c, 254 Mycoses. See Fungal infections Mycostntin, Ste Nystatin Mydriacyl. See Tropicatnide Mydnatics. 573—574

Myelin, 679 Myelogrsplty. 480 Mycloid cells, 197. 981 Mykrox. See Metolazone Myleran. See Busulfan Mylotarg. See (iemturumab ozogarnicin Myocardial ischemia, 622—623. 6231' Myocardial metabolism. 622—623. 6231

Myoscint Kil. See lmcirutnab pentetate Myosin, 623. 6241 Myrtccainc. 6941 Mysoline. See Primidone Mytelasc chloride. See Arnbenonium chloride N Nahilone, metabolism of, 1051 Nabumetone. 759 as prodrug. 152 NAD. 888—889. 8891

NADH. 889 Nadolol, 543, 5441 NADP. 888—889. 8891 Nafantostat. 447 Nafcillin codiutn, 3091. 311—312. See a/co Penicillin(s) Naftitinc hydrochloride, 239 Nautin. See Naftifine hydrochloride Naja venom solution. 835 Nalhupltine, 743, 746, 750 Nallon. See Fenoprofen calcium Nalidinic acid. 247. 248, 248, Nalntefene hydrochloride. 752 Nalorphine hydrochloride. 735. 740. 743. 751 Naloxone hydrochloride, 740, 751 metabolism of, 11)51 740. 741, 751—752

metabolism of, 105 Nandrolone decanoute, 7991', 801 Nandrulone phenpropionate. 7991. 801

Napltazolitie, 533 Naprosyn. See Naproxcn Naproxen. 759 ,netabolis,u of, 114 Naqua. See Trichlortnethiazide Narcan. See Naloxone hydrochloride Narcotic analgesics. 731—753. Ste also Analgesics: Morphine and related compounds metabolism of. 87 Narcolic antagonists, 740—741

structure—activity relatioitships for. 743 types of. 751—752. 752, Narcotic antitussicca. 752 Nardil. Sec Phenclzinc sulfate Nasricort. See Trinincinolone acetonide Nasarel. See Flunisolide Nasonex. Sec Mometasone Iun,ute Natacyn. See Natamycin Natumycin. 237—238 Nateglinide. 671 National Cancer Institute, drug screening protocol of. 392—394, 3931 Natur.,l products, combinatorial synthesis of. 47—411. 471

Naturetin. See Bendroflumethiazide Navane. See Thiothixene Navelbine. Sec Vinonrlbine Imitate Neaminc. 338 Nebcin. See Tobramycin sulfate Nehrsmycins, 340 NebuPent. See Pentamidine isetbionate Nedocromil sodium. 715, 716 Nelazodone. 5 19—520

Nefrolan. See Clorexolone Negorum. See Nalidixic acid

979

NeIfi,tavir. 385—387 development of. 942. 9431 fslembntal, See Pentobar'nital sodium Neobiotic. See Neumycin sulfate Neomycin sulfate. 338 Neonatal hyperbilirubineniia. I IS. 26 Neosamine. 338 Neostigmine bromide. 5631, 564. 56.41 Neostigmine melhylsulfate. 565 Neo.Syttephnne. Sec Phcnylcphrine Nepltrun active ttuhular secretion in, (iOl —602. (,02f

function of in edematous states, 601 in hypovolemic states. 601 in nomtovolemic states. 596—601. 5981—61)01

intercalated cells of, 6(10, 6001 principal cells of, 600. 6001 sodium reabsorption in. 597—601 structure of, 596. 5971 Ncptazane. See Methazolamidc Nerve(s)

fltotoi. 548 somatic. 548 Nerve blocks, 6117

Nerve cells. 679, 6791 Nerve fibers, 679-680. 6801 Nerve impulse, transmission of, 680—681, 6801. 6811. 683 Nervous system

divisions of. 548 structure and function of, 679—685 Netilmicin sulfate. 340—341 Netrontycin. See Netilniicin sulfate Neumega. See Oprelvekin Neupogen. See Filgrastim Neurohoritiones, confomtatiottal flexibility of, 34—35. 341

Neurohypophyseal hormones. 1145 Neurohypophysis. 841 Neuroleptics. 496—503 Neuromuscular blocking agents. 589—595 curarcicttrare alkaloids. 590—591

dcpolarieing. 590 nondepolarizing, 589—590 synthetic compounds with curariform activity. 591—595 Neuromuscular junction. 5119 Neurons, 679, 6791 motor, 680 Nearontin. See Gabapentin Neurotensin, 1155

Neurotrunsinitters, 683—685 acetylcholine as. 548 adrenergic. 524—547. Sec also Adrenergic neurotransmitters drug effects on. 684 excitatory. (184

ganglionic stimulation by. 586, 5871 inhibitory. 684 release of. 1,83, 61141

structure of. 683, 684t Neutralization, in immune response. 205 Neutralizing allosteric niodulutors, 489 Neutropltils. 197. 19Sf, 2t10 Nevirupitte. 383 Newton.Raphson geometry optimization approach, 930 Newton's laws of motion. 933—934 Newton's third law, 924 Nexium. See Esomeprazole magnesium Niacin. 888—890. See also Nicotinic acid as antilipidetitic. 661. 890 metabolism of, 126

980

lnth'x

Niacinamide. 890 Nicalex See Niacin Nicardipine driwhloride. 63 —632 Niclo.amide. 266 Nicotistamide adcn,ne dinucleotide (NAD). 888-88'). 1(891

Nicotinaznide .ideniiie dinuckotide phosphate )NADP). 888—81(9, (4891 Nicotine. 51(7—5(48

ittetalmlism oF. 87. 93, 11)1. 126 Nicotinic acid, 888—890 as antilipidcnaic. 661, 890 metabolism of, 26 Ntciitiiiic receptors. 548—550, 549f. 5491 Nifedipiric. 6291. 630—631. 6311

Nifurtimox, 263 Night blindness, 8711

Nil-I shift. 71. 721 Nilandron, 5cr Nilutatnide Nilutamide, 437. 801—8112. 11021

antineoplastic. 434 Nim.idipinc. 632 as

Niminop. See Nirnodipine Ninhydnn test. 834 Niprtde. See Sodium nitmpnisside Nirsanin. 677

Nisoldipine, 632 Nisosctine, 519 Nitr,utcv. Set' Nitruvasodilators Nitr.m'iepatmm. inelabolisiit of. 107 632

Nitric acid esters, 625 Nitric imuide

formation 01. 624 siwlana and. 283 iii sniooth nmuscle relaxation, 624—625. 6241

Nitrites. Sir Nitrovasodilators Nitro commmpounds. metabolism of. (07— 108

Nitn,funms. 252—253 Nitrofur,mnloin. 252. 253 Nitrofuruzone, 252—253 Nitrogen tmtustani. 394. 399—4(81 Nitrogl5cerin. 625—626. (.251 metabolism of, 12(1. 625 Nmlmmcr,iol. 228 Nitnmprecs. Set' Sodiuni mU'uprusside Nitroso compounds. See Nitrovusodilators Nitnisureas. 395. 398 Nitrous acid esters, 625 Nitrous oxide, 486—487 Nitrova,sodi(ators antianginal action of. 625—626 niechanisin of action oh, (.22—623, 6231, 624. 6241 of. (.23—624. 625, 62Sf

nil.ic oxide release by. 625 i)SldiIIi(ifl State,,. (ii. 625t

speed and duration of action of. 61St structufe—aesivity relationships (or. 6151. 625 types oF. (.26—627. (.261

Nivalin, See Nix. See I'crmcthrin 7(91. 720, 720t. 722 Nizoral. See Ketoconazole n.octauol/water system. drug partitioning in. tY—20

Nodes of Raitvier. 679, 6791, (.81 Nofetunmontab nierpentan. 190

Nonsleroidal anti.influmniatory drugs

Nuprin. See Ihuprolen

Nurum.i..S,'c

us analgesic,.. 753—763. See also Antiinflammatory analgesics

chloride Nutritional factors, in drug mnemabolism. 131.. t32. 944—945

&mruehidonmc acid metabolism and. 822

Nuvaking. Set' Itionogestrel

(NSMDs)

mechanism of action of. 8(8 Nimr.ukenuline, Ste Norepincphrinc Norchloreyclirinc. 706 Noreuron. See Vecumnium bromide Nonlazepato. 490 Norelgestroinin. 7871. 789 Norephedrine. metabolism of. (26 Norepinephminc. 524—547 adrenergic receptors and. 527—528

biosynthesis of. 524—525. 524f in local anesthesia. 688 properties of. 524 structure oF. 524 as sympathomimetic. 532 uptake and metabolism of, 525—527. 5261 Ntmrethindrone, 786t, 7871, 789 in contruccptivcs. 7911—7921 in horrnonc replacenment therapy. 796—797. 7961

metabolism of. (06 Norcthynndrcl. 786t, 7871. 789 Nortlc*. See Orphcnadnne citrate Nmmrlloxacin. 248. 2481, 249 Norgestimame. 7871. 789 in eontr.mceplisc.. 792t

in hormone replacement therapy. 796-797. 796t

Norgestrel. 7861. 787f. 789 in contraceptives. 79lt ntctabolisn, of. 11)1 Norkciamine, metabolism of. 89 Normethadone, 7391 Normodyne. See Labmitalol Normorphinc, 741. 747 Noroxin. See Nortloxacin Norpace. See Disopyramide Norplant. 793t. 794 Norpramin. See Desipramine hydrochloride (9.Nu,flestimstcmne derivatives. 786, 786t Noetriptylimte. 5(7

as active merabolite, (34. l3St Noreasc. See Atnlodipine Norvir. See Ritonavir Noscapinc. 752—753 Notee. See Chkrrul hydrate Novaldeit. See Tanmoxifen

Novuntrone. See Mitoxantrone hydrochloride Novatropine. See l-lnmuu'opine methyibromide Novobiocin sodium, 361—362 Novocainc. See Procaine Novolin. See Insulin, recombinant Novolog. See Insulin, recombinant Novo Seven, Factor VIm, recombinant NPH insulin, 8511, 852. 1(521

NR geometry optimization approach. 930 NSAIDs. See Nansteroidal anti.iullammutory drugs CNSAIDsI Nuhain. See Nalbuphsnc Nuclear magnetic resonance spcclroscopy. of proteins. 832 Nuclear medicine, 455. 458—462 Nucleic acids. See RNA Nucleon, 455

Nyctimlopia. 871)

Isoitiaiid Nystatin. 237. 3(88

(3 9,1 tl-Octadecm,miismnmide. as sleep.tnsntmimting agemtt. 48)1

,m.Oviaimiml/waier system, drug parlituiiiiiig in. t9—20 Octri,otide acetate, 1145 Oculcn.Sm'e l'hurhmprmilemm

(kupress. Si-i' Canemilol Ollonacin. 2411, 248.. 254)

Oil of wintergreen. 754 OK'l'3 Se.' Muronmimah'CD3 Olan,.ipinc, 51)2 Oleammdohidmi. 353

Oleammdotnycin. 353

Olcfmns. oxidation of. 74-77 2' .5'.Oligoadenyhate symithemase. 2(12 Olivm.myciims. 4(7

Olsala,ine enzymatic depredation of. 3 as prodrug. 4-S

.1

Ommieprazole. 722—724. 723i

activation of. ISS. lsf.b Omnnipen. Ste Ampicillin Onini,.can. Sec Gadimiliantide Oncimgenic viruses, 372 OncimScisil. nmurine Sm'.' Saiminutmuab pendetide

()ncnvin See Vincrisiinc satIate One.bL'ad one-conipiiund synthesis. 46—411. 54 62

Ontak See l)enileukmn dilsitox Opiophohia. 731 Opium. 732. 747 Oprelvekimm, 183

Opiical isomers. bimdi,gical .ictisiiy ol. 35—37 351. 361

Optiittark Si'.' Gadoversetaniide Optinmine.Sei' A,atadmne nialeate Optsntizaticin proceshimres, 58

(.)ptiPranolol. Sr-c Metipranimlol Optisiir. Si-c Azela.stine hyilrcmchiloride itplitlmiilmmiic solution

Or.i( administr,itiimn. drug distribution in, 3—S.

4f Oral coimlraceptives. See ('oniraceptives

Orange oil. 229 Oresic.Si'i' flydroclmlorothiazide Organic nitrates. Si-i' Organic mmjtrites, Si'm' Nitnn'itsislitaiors Organoniercuri.mls mnti.inlectusc. 228

diuretic, 610 Orina.se. See Tolbutaniide Onnuse l)itignmr.iic. Sri' Tolhuianimde sodium Ormaplatirm. 4214

Ornidyl. See Efloriiitliine Orphienadrine. imietabmilism mit. 147

Orphenadrmnc citr,ime,5142-583

Orthocainc. 677 Orthocli,ne-OKT3. See Mun,mnonab-('l)3

Nucleoproleimms. 835

Orilmo-Eura. Ste Nimrelgestronhmn

Nog&mlamriycin. 416—417

Nucleoside antifunguls, 235

Orih,mforni. See Orihuicaine

Nolvadex. See Tamoxifen Nminnucleoside reverse Iranscriptase inhibitors.

Nucleoside antinmelabolites. 372. 375—379 Nuclmrscrntes. 835

Orthmmgonah pooling, in eoimtbimtatoeial

Nuclidc. 455 Nnmorphan. See Oxymorphone Nupercaine, 678

Orthmo.Preimisi. Sri' I lomimine replucemmicnl

383— 384

Nonselective norepinephrine reuptake inhibitors. 519

clteittisimy. Sit—SI. 62

therapy Orudic. Sm-c Ketoprolcmi

()sniuirtil. Si" Maiuiiitti) Oirisun. Sec Xyliinieias'oliiie Ovulation, regulation at. 774. 7141

Osacillin sodium. 3i19i. ill Sic tiloi

Papase. Sic Papaiti Papaverinr .586. 732

aiiiispasniixlic activiiy of. 574. 624 iiieiabcilisiii cii. 133

Peuiicilliiiisi Osalid. 763i Onaliplatin, 428 Oxaiiiiiiqiiiiie. 266—267 Oxandrin. See Ovaiidrol,iiic Onandrolone. 799) 11111 Oxapr.iein. 760

Paper chrcnnatiigrapliy. 83.) Parabens. See p-Ilydro.svben,oic acid Paraldehyde, 496 Paraniagiieiic contrast ugenis. 475-477. 476i

Osai.epaiii. 491

Parasvinpadietic agenki. 572—574.5cc into' (')tiilcnergic blocking agenis Panasympaiiici)yiic ageiitr. Sec Otitliicergic blocking agents Par.isympathomiioeiics. 54$

.is active iiictaholite, 134, 135i itieiattolism itt. 133 Ovaaolidinediones. 505 Oxiord unit. 302-3113 Oxiconacaile tiiiraie. 242 Onidiiiiiin in hiotranslorniaiiiin. Sic I)rxig nieiatiolisni. ovidatiiin in pniiein, 73. 74) Oxidaiis e

I lit

Paraplalin. Ste ('ar)xiplaiin Parasyinpailieiic gaiiglia. 586—587.587) Parasyiiipaihciic len-lids sysieni. 518

Parathion. 5711

iiietabiitisin

99

Par.itliyriiii) horniiine. 85.5—856

iiieialritlism 'il. Ill

Oxidatise deantinalion. 89

in vitamin I) synihesis, 876 Par.iths raid injeciiiiic. 855

Osidaiive detiattigeiiaiioii. 1(11 - 1113 l)xidaiise deliydriigenatioii. I lit 85 Osidatixe

Parenterul adniinisiraiicin. drug distrihuiuiin in.

Oxidicing agenis. 223 Oxine. 261

l)xistai. See Onicona.iole iiiicaie Oxisuran, ineiaholisin cii, 14)5—1)16 Oxoinenitirine. 55)1, 5581

Oxy-5. See Hydrous hencoyl peroside Oxy. It) tt' Hydriiiis beiieoyl tieriixiile Oxyhuprocaine hydrochloride. 690—693. 691i Oxychlcircisene sodium, 124

Oxycodiiiie. 733. 733t Oxyciicliine hydroctiloride. 746

Oxy-Coniin.St'i' l)xyciidtine hydriictiliiride Oxyiiieta.iciline. 533 Oxymeiliolinie. 7991. 8(11 Oxynnirphone. 733. 733i. 746 Onyphenhutueaine. as active nierabciliie. I 14. 135t

O.xyp)iencycliiiiiiie liydrociitiiriile. 581 582 Oxypreiiiiliil. ineiabolisiii •i(. 119 Oxyquinoline. 261 l)x)ieirac5cline )iydrccliloridc. 3451. 346— 347 Oxyrociii. 845—846 Oxylocun injeclioii, 84iii. 847 Osyiticin nasal soliiionc. 846) Ocolinone, 615—616. 6151

Paredrine. Sec Flvdroxyaiiiplieiamiiiimc 41, 5--b

Paricalciiol. 879 I,irl.tiisini's disease. 574 l'arnaie. Sec lr.iiis1cs puiiiiciiic sultaie Paroniiimycimi snlfaie. 138— 339. 338)

Pariixeiine. 518 Parsiilc,). Si'.' Ilihiiprcipaiine Imvdnic)iliir,ile Panial agonists, 48') Puma) salo). 755 Particle mesh isisuld nierh.id, 954

Partition coeliic.ent. Il—It. 181. tSr hailitgica) actis ity and. Il 2). 181. 191 Partiiiouiing phenoineita. 18—19 Pasrenrieiiii,in. 2181

Pailciton. Set' Tridihese)IiyI c)ihiriiie Paion r.ite tlieoiy . 572 Paiili exclusion lihiwiple. 937 Pas'nliiim Set' Paiiciiiiniimiio Iironiide l'anil Sr-c Parimnemine Pasipaiii IIa)accpani P('. 17—21. 181. Si I'('lls I pmily c)iliirinaied )iiptieiis Isp. omeiabolusni a), 71 PCP. Sec Plieiicyc)mdmiie ) Iiryihri.niyeimi etlmvlsiieciiiaie Pedianiycin Pedicn)icides. 268 Pegaoiiime. Sic- Iltliiiiiiin PegzLspargase. 429, 43) -432

uidicaacnrs or. 31)7 31)8. 3091 nieclianisin ol acuon of. 3lSli. 3)11—3112 nonienc)aiiire or, 31)3

oral ahsorpiain uI, penict)linase—resistaiui. 3)17

pniperiiesol. 4119) prciieiim binding o),308. 3)0)1 sci)uhi its or, 304

of aclivitv of. 707 30%. 309t siereuicheniis)rs of. 303, 3031 siracrore ii. 31)2i 11)31 ss nlhesis ii). 3)4. 114), 1)161 voWs of. 302— 303 I'emiiciUinase—icsisi.iai penicitliins. 3)17 Ps'nici llina',es,

Penicittiii (;, 4)19_i ))),3))9i Penicillin (1 ben,arhinc.3 Ii) Penicillin 0 procaine.3 Ii) lis.iimcillmim N. 3)8 3t9

Penicillin V.30). 311) Pennyrmiyal. 9)5 Pciuaerviliril,iI iciranurame. iii line,), 61St. 627 Peniatuside. 387 488 PenI.igasinn, 854 I'eiiiaiim 3i81 t'eni.cici,dine isei)iiiiiiaie Pemuianici)is-lnielaniine. 429 Peniaimiidine. (i68 262 t'cnianiidine t'cniaqiiine. 288- 289. 28'if I'enia,ocine. 74)), 741 750-751 inciabolisni of. 8)). 1.41 l'enihi ace__S.', Nleth,isy)lurane I'enudi,,rhii,il. nieiabcilisimi ii), SI Peiitiiliarhiral sinliunt, 4941. 495 Pcnlcislaoi..(i1' Sinlinni sltbi'glaconaie Peniosiutiii. 4)18. 313 liea)iiiftal .Sicdiuni lliiuipenial s.nliuiii Peciinxil .5.',' Peciiaecvt)iiiiicl Ieiraiiiirale. ,liliuied Peiits leiretctra,ote.5 lit l'en Vee. Sec Penicillin V 5,-,- I aiitii)idine Peptarton cc l'eptic acid disease. 718- 71') Pepric acol secre)iiin. 718. 71St Peptides. csntihiiiatiirial ss iitliesis iii, 41, 441, 451

Pepxiids, conihinaioi xi) sy nlliesis .9 43—46. .151. 62

I'erreot ioniiainni. IS Percitdaii

.5.

Osyctidone )iydrcichlarick

Periuclin Sir (spriiliepladine

Pegu.sy&. Sit' Inierferini aba-Ia

Perineurinni. liS)). liMO) Peri1rliei xl iicrs iius sysleni. 541) ),7i)

I'egylated inierteriiim allu-2a, 18)1. 1816 Pellagra, 89)1. 89)

Iieriirae.,S,. Periiaemy ihritiil teiraiiuriile. diluted

Peniirolasi porassiuni ophilialinic soluiioim. 7 16-7)7

Pernr.qx'ii Sit Peimit ilIum I beneathine

2-PAM. pmdrug foriii ci). 157- 158, 1581 Pamaqiiine. 288—289. 2891

Penmtt)ine,514

Pumelor. Sic Nortriptyline Panado. Sic Aceiaminophen Pinion qciiiiqiii'Jinlini ginseng). 9)3 Puncreaiic hiiniioiies. 847—854 Pancreaiiii, 838, 839i Pancrelipase. 838. 839i

Penhriien. See Anipicil)iic

Pciuieilinn. 21i8 Iieriiiiiil Sc. Flmi1ihenaiine hs ilriich)oride Periiiciun,s .nienoa. 895

Peiibnumli.). 54

Pcrphenaeine. 4991. 5)8)

p p53. 391

PAIIA. Sic p-Aitiinobenniic acid iPAHAi Paclitunel. 425. 427—428, 915 Pain, types of. 73)

Paiicreoeymin. 854—855

Panvnroniiini bromide. 593 Panmycin. Ste Teiracyctiiie Paitietiti. Sec Aliireiinoin Panteric See Pancreaiiii Paiiihen,iI. 888

¶441

Penciclovir. 378 Peneirex See Entinacin

Persanhne. Sri Oipyridaiii,ile

Penlliiriilii). 50)

l'erionat. 72. 76)) l'ernur)saiani nieiltiids. 93')

I'enictllini s) 102— .11') acid resistance if, 3)19) acytnreids'-suhshiuied. 308 allergy to. 31)8- 7)83 bacterial resisiaimce to. 1)15 31)7 $4aci.mm.ise inhibitors xsiltm.3 14—315 classificaiiim of, 3119, 1l)9i

Paniopracote sctdcnin. 722. 7234. 725—726

clciniliercia) prodntinni il .31)2—3)).)

Puntoilienic acid. 887 888

degrailatisni of. 31)4 31)5. 3)16) i)msci'sery and dese)cipineiii iii, 2403 exieni)ed-specinicii.3))7 - 3)18

l'apain. $411

tic action iii, 837. 8371

Peritifraice. Sec l)esiliraniine )msdrutclc)oride

Pesticides. close nieiabolisini aiid. 13)

Pesi,in III 5,-c PET i piisiiroii emission ii'iiiogruphy I. -156. 4641

460). 4lilf I'rosiagl,niilinis PG syii)he)ase. 8)9

POll.. $2)) P0)4 s5 iilliase. 8)9 82)). 822 p1)1. 82))

dcriratixes ii). 823 825

982

Index

P-glycoproteins, in drug resistance. 392

Phenylcarbinol. 229

p11

Plsenylephrine, 532—533

calculation of, 13—14

vs. percent ionizoion, IS plC,, and. IS—lb. 151. IS Phage vectors. 165—166. 1661 Phagocytosis. 197—198, 19Sf. 204—205 Pltagolyssssomes. 197—198. 1981

97. 19Sf Pharmacogenomics. 193 Pharmacognosy. 905 Plsnrtnacological activity, statistical prediction of, 17—26 Pharmacological screening. See Drug design; Screening Pharmacophore concept, in drug design. 944 Phemerol chloride. See Benzethonium chloride Phenacaine hydrochloride. 694t Plsenacetin. 761t, 762 active metaholites of. 135t metabolism of. 98, 116 Phenadoxone. 739t Phenazocine, 740 Plsenazopyridine. 253—254 metabolism of. species differences tn 129. Phagosomes,

1291

Phenbenzamine, 704. 7(15 Phencyclidine (PCP). 52(1. 521

ntclabolivm of. 82 psychosis due lo. 497—498 Phcndintetrazine tartrate. 514 Plsenelzine. metabolism of. 122. t23f Pheneleine sulfate, 515. 51St Pltenergan. See Piosoethazine hydrochloride Pheneridine. 73ht, 737 Plsenetidine. bIt. 762 Plsenetsal. 761t

Phenlormin. 668 Phenindamine tartrate. 709—710 Pheniramine malease. 708 Pttenimmines. 707—710 Phenmetrazine, metabolism of. 89. 101 Phenobarbital. 494. 4945 as anticonvulsant. 504

as ansiolytic/sedative-hypnolic. 494, 494t drug intrmctions with, 131 as enzyme inducer. 131 metabolism of, 70 Phenocoll. 761t. 762 Phenol(s), 217. 221—223 corrosiveness of. 14—IS

glucuronidatiun of. 115 liquefied. 221 tnethylaiton of. 12$— 126

2-Phenylethanol. 229 Phenylethyl alcohol. 229 fl-Phenylethytamine. structttre—activity relationship for. 530—531 5-Phenylhydantoin. metabolism of. 109 Phenylmercunc acetate. 230 Phenylnsereuric nitrute. 230 Phenyltnethanol. 229 Phenylpropanolamine. 538—539 Phenyl sallcylate. 756 Phenytoin sodiunt, 505. 5051

Pituitary gottadotropins. 774—775. 7741 Pituitary homsones. 841—844

Pisalic acid pmtniety, 145. 14Sf 13—14. 14t, 1St

acid/base strestgtlt and. 14 drug distribution and. 16—17 percent ionization and. 15—16. 1Sf. lot pH adjustments aitd. 15—16. 1Sf. lot values for. 948t—956t

as antianhythtnic. 639-640

water volubility and. 16 Placental barrier. I' Placidyl Se,' Ethchlorvynol Planch quantans theory, 935—936 Plaquenil See

as anticonvulsant. 5(15. 5(1St

Plasmakinitss, 85(s—857

interaction of with isoniazid. 124 metabolism of. 70. 124. 132. 133 species differences in. l28 pHisol-lex. See Heaachlorophene Phleomycins. 417 Phosphate esters, as prodrugs. 149. 149f Phosphocol. See Chromic phosphate P 32 Phesphodiestemse S inhibitors, active sites of. 29. 31)1

Plasmid vectors, 165—166. 1661 Plo.smod/son ui-oh'. 282, 283—285, 2841 Phu.srnor/iiuns spp., 282. 283—285, 2841

drug action against. 284—285 genisnte iii, 285 infection by. 284—285. 2841 Si',' rats,, Malaria

life cycle of. 2841 types of. 283

Phospboinositol systesn. 552 Phospltoline Iodide. See Echothiophate iodide Phospholipase C. 552 Pltosphoramide mustard. 396. 3961 Phsssphorothionatev. 568 Phosphonts-30. 457 Phosphorvlation

Plassusodhum error. 282. 283—285, 2841 Platetetis)

in DNA synthesis. 154f. 15Sf of ptsidmgs, 153—154. 15Sf Photodynamic therapy. for cancer. 430. 433 Photoelectric effect 936 Photofrin II. See Portimer sodium

Platinum consplexes. 428 Platomycins. 417 Plavix.S,'i' C'Iopsdogrel Plegine. Si-c Phenditstetra.rine taflrate Plendsl.S,'e Felodipine Plicamycin. 414, 417, 424 Pluripotestt stein cells.. 177, 17Sf. 197. 19Sf PM3 method, 938 Pneumocanadins, 246 Pneumococcal vaccine, 215

Plsysostigmine, 563—SM. 563t. 5641 Physostigmine salicylate, 564 Physostigmine sulfate, 564 Phytoesteogens. 778—779. 77sf Phytonadione. 884—885 mettadlisne conversion to. S

Picrotoxin. 510 Pilocarpine hydrochloride. SoIl Pilocarpine nitrate. 56(1 Pimaricin. 237—238 Pitninodine, 736t. 737 Pimoride. 501 Pindolol, 543, 544f Pink disease. 891 Pinocytosis. S

fibrinogen receptors 'itt, 633—634 functioits of, 665—666 Platelet aggregation. 665—667. csobf inhibitors of. 666—667 Platinssl. See Cisplatin

P,ieuunou'sstis ,'ocunhi, 264)

Podophyllotissin, 424 Polaratnine.S,'e Dexchlorphetiirasnine malcats' Polani'alissn functissns, 938 Pisling algoritltists, 933 Polio vaccine, 2111, 212t Polyacrylamide resins, in costsbinatorial

chemistry. 49 Potychlorinated biphenyls (PClls), metaholisas of. 71

Phentermine hydrochloride. 513 Phentennine ion-exchange resin. 513

Pins, in combinatorial synthesis. 44. 4Sf. 62 Pinworm infestation.s. 265 Pioglitazone. 672 Pipanol. See Triheayphenidyl hydrochloride Pipecurittm bromide. 593 Piperacillin. See rats' i Penicillims spectrunt of activity of, 31)8 Piperacillin sodium. 309t. 314 Piperacillin-tazoboctam. 316 Piperazine estrone sulfate. 780 structure of, 777f Piperazinelsl. 265. 706—71)7. 706f Piperocaine hydrochloride. 690—693. 69lt Piprucil. See Piperucillin sodium Piranthicin. 416 Pirbuterol. 536 Piretanide. 61 If Piritresim. 410—411

Phentolamine. 539

Piroxantrone. 429—43(1

Phenylalanine. hydrogen-suppresved. 23—24.

Piroxicant. 760 Pitocin. See Oxytocin injection Pitressin. See Vasopressin injection

49 Polythia.cide. 605—(sltt, (Slot, bUst. 620 Pondimin See Fenflurastsine hydnw(tlondr Ponstel. Sri' Mefestatnic acid Porfimer sodtusn. 43tI. 433

Pitressin Tannate. See Vasopressin tannate

Porliromycin. 419

Pituitary antidiuretic hormone. See Vasopressin

Porlamines, 533t

topical. 234—235

Phenol coefficient. 221 Pltenntlsiazines anlihistansine. 7111—711

antipsychotic. 498—500. 499t metabolism of. 87 ring analogues of, 499 Phenoayacetic acids. 613—615 Phenoxybenzamine. 540 Pttenonymethylpcsticillin. 310. See ratio

Penicillin(s) Plsensusimide. 505—506 metabolisttt of. ICY.) Phenteemine. metabolisnt of. 91—93

24f. 24t. 25t Phenylbutazone. 762. 763t active melabolite.s of. t34. 135t metabolism of. 70. 82. 114

Polycillin. See Ampicillin Polycyclic aromatic hydrocarlxsns. carcinogesticity "I, 74. 74f Polyene antibiotics iS—238 Polyethylene glycol. in combinatorial chemistry, 49, 62 Polymerasc chain reactiost. in combinatorial chemistry. S2. 62 Polymer heads, in combinatorial chesnistry, 48—49, 6(1

Polymos. See Amoxicilliu Polymysin B sulfate, 357—359 Polymyvins. 3(Xlt. 357—358 Polypeptide antihiistics. 355—36(1 Polysaccharide-coated superparaniagnetic trots

"side particles (SPIOsI. 477 Polystyrene resitis. in coinbinatisrial

Indev Procainamide hydrochloride. 638

Pocaconawle. 244 Posicor. See

Mibefradil

Procatne. 678

Positional cloning. 167, 167t losiuonal scanning. 51, 62—63 Positive inotropic agents. 655—657 Positron emission. 456 Positron emission tomography d'ETI. 456. 460. .1601. 4611 contraceptives, 794—795 Potassium channel openers. 654—655 Potassium ion channels. 681—683,6)121. See also Ion channels Potassium leak channels, 681 Potassium sorbale. 230 Potassium-sparing diuretics. 616—618. 6161 preparations of. 620 Pswidone-iodine. 223 Poxs'i,uses. 3701, 372 Pradimycins. 246 Pralidoxime chloride, 571

Ptatnoxine hydrochloride. 694t Fl'jndin. See Repaglinide Pranral. See Diphcmanil methylsulfate Petsachol. See Pruva.statin Petsastutin. 663 Ptaarpam. 491 Praziqnanlel. 267 Ptazosin. 540—541, 541t. 652

metabolism of, 98. 109 Preccf. See Ceforanide Precipitation. 175 PSecose. See Acarbose Ptednicarbate, 81)111, 813 PSednisolone. 811 metabolism of. I 10

relative activity oF. 8091

ioluhility of, 770t structure of, 807f Ptminisolone NaPO4 salt. solubility of. 7701 P(ednisone. 1111

active nietabolites of, I 35t as antineoplastic. 435 relative activity of, 81)91 Pregnancy

hCO in. 775 placental bamer in. 6 Pregnenolone. in steroid biosynthesis. 768. 769, 7691

Estrogen(s)

Premphase. See Hotmone replacement therapy Prempro. See Honnonc replacement therapy Preservatives. 228—231) P(rvacid. See Lancoprazolc

Priltacaine hydrochloride. 690—693. 6921

Ptinucor. See Milrinone Pemaqaitie. 288—289. 2891. 295, Fhnuiy pulmonary hypertension. 823—825 Piintasin. See lmipcnent.cilastin Plimidone. 506 active metabolitcs of,

Prnchlorpcra,.ine malcntc, 4991. 5(X) Procrit. See F.poelin thu Procyclidine hydrochloride. 583—584

Prodilidine. 737,, 738 Prodrugs. 109. 142—159 activation of. 142—144. 152 by azo cleavage. 149—ISO. IS It' chemical, 155. 1561

by oxidation. 152 by phosphorylution. 153—154, 15Sf by reduction. 152—153. 1531 advantages oF, 142, 154—155

alcohol promoicty for. 144—149. 145f—l491 amine, 149, 1501 azo linkage and. 149—150. 1511 binprecursor. 142. 143. 152—155 in cancer chemotherapy. 156 carbonyl pronsoieties for. 150—152. l5lf cartroxylic acid promoiety for. 144—149, 14Sf— 1491

earner-linked. 142—143. 145—152 as chemical delivery syslents. 155—159. 1571'— 1591

definition of, 65. 142

in immune response. 205

Premarin. Sue

Procaine hydrochloride, 690-693. (,9lt Procan SR. See Procainamide hydrochloride Procarbazine hydrochloride, 397, 402 Procardia. See Niledipine

35,

Principal cclii, of ncphron. (rOll Principal components analysis. 511. 63

Ptincipen See Ampicillin Ptinivil. See Lisittopril P,i.scoline. See Tolnzoline Psistinamycins. 363 Ptisine. See Naphazoline ProAntaline. See Midodrine

Pto'Banthine. Sri' Propantheline bromide Plirbenecid. metabolism of, 70—71 Probucol. 662 Plocainamide. 638

active metabolites of. 135,

metabolism of, Ill), 122. 124

double-ester, 146—147. 14Sf drag distribution and. 4—6 ester. 144—149. 1451— 1491

of functional groups. 144—152 hydrolysis of. 146—149 Manniclr bases and, 149. 1501 metabolism of. 142. 146—149 mutual, 142—143 prornoieties and. 142 solubility of. 5. 142. 145. 147—149 For unpalatable parent drugs. 145—146 Productive infection, 367 Product stereoselectivity. 103. 132—133 Proencymes. 837 Progestasert IUF). Si'e Progesterone IL'D Progesterone

as antineoplastic, 434 biological activity of. 785—786. 786, biosynthesis of. 769. 7691'. 785 formulations of, 788 metabolism of, 785. 7861 structure of, 71171

Progesterone (UD. 793t. 794 Progesterone receptors. 773 Progestins, 785—789 as antineophistics. 434

biological activity of. 785—786, 786t biosynthcsts of, 769. 7691, 785 in contraceptives. 779. 790—794. 7911—793. endogenou.s. 785

itt honnone replacement therapy. 796—797. 7961. 7971

metabolism of, 785, 7861' products. 787 progextational activity of, 786. 786t structural classes of, 786. 7871 synthetic. 786 therapeutic uses ttf. 787 Proguanil and atovaquone. 29lf. 292. 292f ProHance. See Gadotendol Prohcptazine. 738 Proinsulin. ((47, 848f. See also Insulin, recombinant Prolactitt. 844

98.3

chorionic growth.hormone. 845

metabolism of. Ill Prolurtin—releasing hormone, 841 Proleukin. See Aldesleukin

Prolixin. Fluphenazine hydrochloride Promazine. 498, 4991 Pronicihazine hydrochlortde. 710—711 Prometrium. Progesterone

Promoietics. prodnig. 142 Promoters. 168 Prompt insulin zinc injection. 1(5 It Pronestyl. See Procainamide hydrochloride Pro,tethalal. 542 Prontosil. 149. 1511. 269 Propacil. See Propylthiourncil Propadrine. See Phenylpropanolamine PropaFenone. 64(1—641

2.Propanol. active metabolites of. 220 Propantheline bromide. 582 Pruparacaine hydrochloride. 690—693. 691, Propecia. See Elnasteride Properidine, 7361

Propine. See Dipivefrin Propionic acid. 233 Propofol. 488 Propoxycaine hydrochloride. 690—693. 691, Propoxyphene. 738. 7391

metabolism of, 85 Prxtpoxyphene hydrochloride. 749 Propoxyphene nupsylate. 749—750 Propranolol, 542—543 active metabolites of. 135t metabolism oF. 70. 89, 103, 112—114. 114 Propylamines, 707—7 10. 7(171 Propylhexedrine. 5311

Propyliodone. 484 Propylparnbcn. 229 Propyl p.hydioxybcnroate. 229 Propylthiour.tcil, 674 metabolism of. 114. 126 Proscar. See Finastende ProscWOS. See Phenyl salicylate Prustucyclin.slerived drugs, design and development of. 823—825. 824t—825t Prostaglandin(s). 666—667. See also Eicosanoid(s) antiulcer. 726

biological activity of, 822t biosynthesis of, 8 18—822. 8191. 8201 in coagulation. 666—667

discovery and development 01'. 818. 8I9f. 820f metabolism of, 82 If. 822 Pl'ostaglandin unalogues design and development oF. 823—825, 824t—825t invesligational. 824:—825, ophthalmic. 823. 828

Prostuglandin 01. 1(221 Prostaglandin E1. 822t. 827 Prostaglandin E1 cyclodextrin. 827 Prostaglandin 8221. 827 as abotlifacient, 795, 7951 Prostaglandin F1, 822t Prostaglandin F1,,. 827 as abortifacient, 795. 7951 Prostuglandin H2. 820 Prostaglundin 820. 8221 Prostaglandin inhibitors. 754 Prostaglnndin J1. 822, Prostunoid receptors. 825—827, l126t Prostanoids. for vetennary use. 828—829 Prostaphilo. See Otiacillin sodium ProstaScint Kit. See Capromub pcndetide Prostat. See Metronidazole

984

len!,'.;

I'rostate cancer anliandrt.gens lot. 801—802. 8021 estrocens for. 779

l'room E2 S..' l'r.istaglan.Itn F.. Poisiji, P2 Alpha. Sec Proslaglandin p:,. l'rostin VR l'ediat. it l't.isiagl,.n,lin I., Pr,.taniines, 833;

Protat,,tne suII;ite, 667 I'rotaintne tune tisnlji, suspensuin. sS tt. 852. 852t

Protease catalysis. 837. 8371 Protease inl,ubn,,ts anti-I 11%'. 184 —l$7

I'rotruptyline hydrochloride. .S 17

I'r.itropin. S.. .Si'ntatretu Priveinil Set- Alhuier,,l Pnn-era. S,, Medr.rxyprogesterone acetate

in snhstitueni selection, 22—23. 23t threeitiunensior,aI. 21.18—19 Quadrainet Samarium SM 53 lex,dronarn Qua,,titatise sun.ett.re—acov.ty relaliu'nship

I'rorigil S.c M.nlaftnil

IQSARI. hl—21 See of." QSAR

l'n't itanot, A. 869—87)) Pri's itanuitr I). 875

studies Quauuintui dots, 53

l'r.',ac See Ilt.oxettue

Qt,.,titt.ni ,neehaut,es. 38. 923 in compttter-assisled drug design. 935-939 Quarean Ctidittinuo bromide

l'seu.d..chuoltnesteru.'.e. 564)- 56), 5611

4- ).Psett.Ioepltedriiie. 538 Psead,.n,,.n.,I i,ttect,,,ns air.tut..gtyc..snte-rrsisiat.I. 336

ceplralosporins ti'r. 325. 326t fl tactain-resisiant .32.1 Pseu,t,t,rumtc acid A .362—363

Qua.eeparo. 492

Questran. Si-c Clu.lesuyrannne resin Quetiapune. 5112—51)3

h'seudouropune. 575

Qninacrine hydroct,I,,ride, 293). 294 Quinagtute..Se,' Qt.unidine gluconate Quhrtapril 646. 647). 6471

acute phase. 2))). 21W

Ps,l,win, 521

Quinelhartine, 6(17—6)0. 1,4171. Ôtt9t, 62(1

apgn,gati,.,u il. 175

Psilocyhiti. 52) Psyctt..ses. 496 498 t'nturrcort t,.rh,,l.alcr. See Budeso,,ide

Qitinidine. 286, 286). 287. 295t active ,,tetabol.tes ,ut. I 1St tttetab.,I,sm ol , 77 Quit,i,Iine gluconate. 638 Qainidine 638

ileuel.'pment iii. 942. 9431 ant.neoplasuic. 446—447

Protein),. I. S.. .,l,,' Recepi''ris

.itnpholeric behavior itt. 833 of. 173. 174$

Iiltkitl. 857 858 buried. 833 cheunislr) of. 173-175. 1711

chimenc. 168-169 in dote screening. 172

c..nkirmatn.n ii 831 —832. 8321. 815 doug—receptor iutteraclii,ns ''itt. 28 conjugated. 833 deanodat,on of. 173. I 74) denatnr,,Iuon Of. 173- 175. 833

tirceulation ol. 175 fusion, 11.8—11.9

in .Intg screening. 172 hydn.lysis 4,1. 173. 17.11

hydrophobic Force' ii... 831

instability .'I chemical. 17. 1711 physical. 171 175 oxidat..... il. 171. 1741 piattranslational nh,nJiI ieali,,uis iii. 162—Il,). 1631

precipilar.u'n ot. 175 products. 814-835 properties of. 833 pnriticatu't. 4,1. 833 race.,uaauiou .8. 171. 741 reco.nb,na,ti. 11.8— 169

immun..gen.city.uI. 175 separation and ideu,tilicati,',. itt. 814 simple liruel. 811. $33. 813t soluhility $33. $13t structure of. 162. 71. 811-833. $IIL 8121 ,Iatahasec iii. 39- 41) Factors alfrct.ng. 832—833 surface adsu'rpti.'n itt. 175 synthesis ot. 62 63. 1631

Protein

I',,, if.ed c.un.c..tr..pun. Sir Reposit.'ry ctirttcotropin injection l'urine nucleotides. the n,,v,, synthesis of. 4)12 -4184, 41)3) —41841

1133 classiticutu.'n color lesus 1w. 834

Protein binding. I. 7 Protein C. 665. 883 Protein c.'y.nes. S,'.

h',,h,r,,,,,arv hypertension. 823—825 ne. See Dontase alla

P,,,iu,etltol S.',' l.—Nlercapl..lrarine l'Vi'-sutir,e St. I',.s

I'r.tli.I.'xi.,te chl.'nde I'r..tu.porphvrin IX. it cvtoclrrotne I'—451l. 67 Protriplyline. inetabolistu ol. 76

Prurroparn chloride

Qninu.lumes, 247 -252

properties of. 247 -248. 2491 types iii. 248 -252 Q.nnoplrenol. 261 Qu,unosol 5,'.-

I'> taa,,tid,,re. 7t.2 t'yrae.il.ihuned.nne der,v,,tives. 762— 763, 7(.3t

K

i'sran'lit,e. 762 Psran.l.,,,e ,teiivaiives. 762 ibe.t,ar.,ine citrate. 705 l'yr.tttne. ninhrydrin lest for. $34 I'y odi.,n;. Ste l'hetuan.pyri.litte Pvrid.'stiguuine bromide. 5631. 565 Pyridt'x..t. 89) Pyridoxal 5plt..sphrate, 892 —894 i.l..xan,ine. $91 Pvrid..xine. $91 —894

deliciency oh. 8')) dietary s,iuree.s of. $92 drscosen il, 89) h,,,ntones ti,,), 893 -894

Qninnpristin-daItoprrsuin. 363 QVAR i'. I(eclotrrethas,.ne diprurpionate

Rahepra.eole sodit,n,, 722. 723r. 726 Kacemic catciutni panrotl.enate. $88 Kacemic mintnres. ntetatb.'tisnt of. t 32 Raeenti,ati,.u.. protein. 171.. 1741 Racem,.ran,idr. 738. 719, R:icetruorphan. 738—719, 75(1

Radanil.S.'e Ben,nida,,.le Radiati,.n. 454- 458 atuttittitati,.t,. 456 hiologucal etlects ut. 457—458 delinitiurn of, $54 direct effect utI. $57 ehectrounitgnet.c. $54

indirect ellect of. 457 ionieing. 454, $51 properties of. 454—451.

.uI, 89) —$94

t'vrud..xine hydrochloride. 894 Pyndost'l. 892 P5 rilanuine ,i,aleate. 7115

I'yrunrethanrine, 27) I'ynrnetltamine'snlfaduaeune. 271tt 2891—2911. 2911—292. 291,1

I'yr.n.idtne urncleosi,le antagonists. 40$. 41191

l'yr''nil .5.'. Pyrrobutantine phosphate P/i insulin. %51t, 852, 852t

r.idioactive utecay intl. 455 -$57 Radiati,,,, ,thsorbed dose. $57 Radiation dosu,netr . 457 Radi,,activr decay. 455—457 Radiotrequency enciuding. 53 Radi.'gntphy. 472 -473 Kadioh..gic pru.cedures. 478—481

cintirast agetits tiir. 472—484 Radiu.pharmaceutieals radiotraeers For. 458—472

Radionuettdes. $55. 457—462. Se,' olin Radnuphtaritraceuuueals daughuter. 455

sates. 8311—831

Protein kinases. in tnnt.'r.geuesis. .138 Protein S. 883 Protein tyrosine Ltnase iulrit',uns. 438—441) Prote.rnties. 193 in dn.g developnreni. 44') I'r.rthronrhin, 663. 664. 664t. 64,41. 665 I'r,,tonix c i'anropra.'ote sodit,rrt Proton pump inhibitors. 722—726. 7231— 725). 721i activnt,.urt ol. 155. 1561

Quinine. 286-287. 2561, 295t

Py.'pen S,, C'.irtrenicilhiu, ilis...t.uitr t''.r.ii.tel patit.xtte, 265 I'yr...'inamtde. 254, 255 256 l'yraeinecarbosamide. S.-. h'yra,inatnide l'yraioles. 762

Ps rrob,tla,nine phosphate. 741') tries

Qatnidmne salIate. 637—638

Q QSAK studies, 17-23 bilinear tumId in. 21 - 22. 2)1

lis-e-di,ne,,sional. 23 tHur—,lintensi. na), 21

tdentitv variables in, 23 linear trunlel in. 21 -22. 211

',,ieut,,,tlwater system in. 19 lIt

parent. 455 production itt. 461—462 pttiperties .4. 454—456 Irttnsf,,rnratiuin itt. $55 —-157 Radninuchide test kits. monochonat antitnnty. 190-191 Radii.phartnacettuieals. 454—484 contrasi aget.ts. 472 —$84. See ,ti,o C,,utrusu agents

parabolic model in, 21—22. 2)1 pantiton coeltic,ent un. I 9—21 pltysicochemucat par.mreters in. 21. 211

t)u.'ritte. 468 gallium. 468

predtciive pln.rniacoptu.ne u.a.utels and. 944

iodine, 468-469

indium, 469- •171

moituclonal atttih'tdies. 47))

Reconthisas. 186, 86(lt

radiotracers. 458—472 leehnetittm. 462—41,7

So-Rednctase inhibitors, 802—803, 81)31

thalliam, 472 venus. 472 Radiotherapentic agent'. 444—445 Radi,.qruccrs, 458—472.3?,' a/xe. Radiophanoacenticals Raloxifene. 7811. 782. 783 actutttts uK 29

Ramipril. 6471. 6$7t 648 Randottt screening. I Ranüidine. 7391 72)), 720t. 721 —722 RAREs. 872

Lit protein. 438—439 Ratio 1.5 contntst agents. 473 Ratio 3 contrast agems. 473 Rational dntg design. 1—2. 919. 92)). 940. Set' talc,, Drug design Randisitt ci. Rattwolita RanSed. See Kcserpinr Ratiserpal. See Ranivitllia Rausal. See Rauscolita Ransst,Ilia. 650 Rutot'oif,o si'ep.'ittiiio. 651)

Rayderm See I'henyl salicvlatc rDNA technology. 163- 194. 858- 86)1. 859t. S..i' also IIiotecltnolttgy in receptor isolatiott. 28 step' in. 858—864) Rehutsetinc. 519

Receptoos). 8—9. 27—29. Sit a/s.' specific t)714'.s

allinity 1,tr. 8 a.syntuttetry "I. 35—37 chiuneric. 169. 1691

clotting of. 28. 172.S.'.' ia/so Cloning distribution of. 9. 28—29 drug ltindittg by. 27—28 virtual screening for, 55 drug interaclions with. Ste Drug—receptor ttderacttons

flesible. 28 as lutactional areas. 28 heterttgcnetty ol, 169- 171). 17))t

isolation of. 28 ttteittbratte-hotttid. isttlation al, 28 t,r.etttation of, 28 properties iii, 27—29 specificity of. 28 structure ttf, databases of. 39—40 variability itt. 28—29 Receptor-baseti drug design. 55. 939944 Receptor '.election and antplification technology lr-SAT assay. 171 Receptor tyrosiute kinase inltihitors. 438—44)) Recottthinant DNA wcltttolttgy. 163—194. 858—864). 85')t. Ste a/si. Biotechnology

DNA processing in. 172, 860 DNA production in. 364. 166-168. 860 in receptor tsolatiott. 2$ steps in, 858- 861) Recombinant drag prodttcls, 859t—sotlt. 864)—863.Sre ,,lso Biotechnology ond u/ie.'tfic prts/zat-cs

ADME propeoies ol. 175 hioasailahthity ii), 175 drug delivery ot, 175 tttctabohism of, 375 types of. 175—191 Recounhittatti proteitts. 168 — 69. Se,' ,,ts,'

Ilio(echnology immnnogentcity of. 175 pruwes.sittg of. 172

Recotnhinate. Set' Factor VIII, recotohittant

Redaction, tn biotransformation. See I)rug metabolism, reduction in Redun. See I)esfcnfinratmine Regional nerve blocks. 687.5ev ia/ut Local anesthetics

Rcgioselectivity. itt drug ntetnbohistn. 133—134 Regitine. See Phentolamine Regranea Gel. See Becaplerntin Regular insttlin. 853. 85 It. 852t Relalen. See Nahumetone Remeron. See Mirtantpine Remicade. See Inilisintab Retttifetttunil hydrochlonde. 748—749 Reminyl. See (lalantumine Retnodulm. See Trepro'attnil Remosipride. 502 Renal drug eacte)itttt, 41. 8 Renal Failure, drug metabolites in. 134 Renal solute reabsorption. 596—601. 5971—6001. See also Nephotn

Renal tonielty. nI sulfonantides. 122. 274 Renese. See Polydtiazide system, in blooni pressure regulation, 642—645, 6431—6451

Renin•angiotensin system inhibitors. 645—646. 6461

RmuPru'. See Ahcisltnah Repagltnide. 671 Replicons, 165

Reporter genes, in drug screening. 171-172 Repository corticotropin injection. 842. 842t Rescinnamine. 529 Rescriptor. See Delavirdine Rescula. See Unoprostone Reserpitte. 529. 65)). 6501 Reserpoid. See Reaerpine Resitts. in cotnhinatorial synthesis. 48—49, 481. 63 Rcsorcinol. 222. 233—234 Resiasist. See Ferrisan Respiratory hurst. 203 Resting potential, 68)1 Restoril. Temazepam Restriction endonucleases. 164—165. 16Sf.

lost. 860 Retepla.s'e. 184, l84t Retevase. See Retepha.se

Reticaloendothelial system. 198—200. 199t Rettn-A. See Tretinoin Retina, vitamin A and. 871—872 872. 8721 Retinal, biosynthesis of. 879 Retinoic acid, 867. 870 biological activities ntf, 872

Re Via. See Nahtreat,tte Resitlate. See Snuliunt tltto.sahicylate Rhtnocort. See Bttdesonide Rhodutpsin. 871. 872. 872f

Rhythttttd.Se.' Potpafettone Rihavirin. 381—382 Riboflavttt, 89(1—891 Rchard.san approach. 922

Rtt'abutin. 257. 258 Rifadin. Set' Rifatttpin

Rifantpicin. See Riltmpin Rilampin. 254. 257-258. 300t Rifamycins. 257—258

Rintactane Ste Rtfampin Rimantadine, 372 373 Riuttemtlotte. 8 lIt, MIII. 833 Ring equivalents. 43 Ringwornt. 23)1. 233. 231t. 233—235 R istitner. 35—36, 371 Risperdal. See Rispcridotte Risperidtttm. 497, 501 Ritalin. See Methylphenidate Ritodrine. 537 Ritonavir. 385—387. 942 Ritsert. 678 Ritasan. See Ritusimab

Ritusimab. 389. 443. 444 Riva.stiguttine. 567

RNA. 362 anttscnse. 393— tM modeling of. 92(1 RNA viruses. 368t. 369t, 371 —372 Rithasin. See Methocarbanttl Robinul. See Glycopyrrolate

Rocephin. St', Ceftriasone disodium Rocttagan. Set' Bettznidantlc Rods and cones. 873. 872 Rofecttsib, 760. 822—823 Roferon A.Se.' Interferon ahla'2a Rohitetoucycline.345t. 346 as po.drug. 149. 151)1

R,atnilar. See l)csurotttetltorpltan ltydrthrotti Rondotoycin. See Mcthacychinc hydrochlori Ropivacainc hydrocltloride. 69(1—693. 692) Rose oil, 229 Rosighitazone. 673-672 Rotasirus vaccine. 213 Rotrecctgitt alfa. 185 Rttandwortn infestations, 265 Rtuaiam. Set' Rcmosiprude r-SAT assay. 171—172 RU-486. See Mifepristu'ne Rubella vaccine. 214). 212t

Ruhidomycin. See Daunombicin Rule of Ose. Lipinsku 40. 55. 62 Rynatass. See Carttetapentatte citrate

unetahohism atE, 1)69

Retinoic acid receptttrs. 872 Retinttids, See a/so Vitamin A antineoplastic activity of. 430 delinition of. 868 Retinoud X receptors. 872 Retinol, 868. See u/to Vitamin A absorption of. 869 esterilication of. 869 unetabolism of. 869 all-teana-Retinol. 867. KitE biosynthesis of. 872. 8721 Rerinol-binding protein. 869 Retroviruses. 371 —372. 380 Reverse tr.mscripta.se inhibitors, 372, 379—38) nt,nnucleostde, 383—384 resistance to. 382

Reverse truutscription. 371 -372. 380 Reves. See Nalmelene Itydrocltloride

S

5-145, 824t Safety—catclt ltnkcrs. un conthinauttrial synthesis. 49. 63

Sairole. tnetabolisnt itt. 80-SI Saint John's won. 908—910 Salbutamol. tnetabolism of, 87. 115 Salcto. See Salicylanutde Salicylatttide. 756 Salicylanilide. 764). 76lt Salicylic acid, 233—2.4. 754 ntctalxtlisnt of. 114, 117 Sahicylic acid derivatives, 754 —757 Salk vaccine. 211). 2l2t Salnieterol. 536

Salol principle. 755-756 Salsalate. 757 Saltatory cttndactiu,n. 680

986

hider

Suluron. Sec Hydrotlumethiazide Samarium SM 153 lexidronam. 444. 445 Sandostatin. See Octreotide acetate

Serum globulins, 857 Serzone. See Net'arodone Sevotlurane. 486

Sandril. Sec Res.erpinc Saniti,aiton. 2 I St Saquinuvir, 384 development of. 942. 943f Sargramosttm. 179. 430. 432—433. 859t, 863

Sex differences, in drug metabolism. 129—13(1 Sex hormones, 775—7119.5cc also Steroid(s) biosyttlhesis of. 768—770, 769f. 775 in chemical contraceptives, 7$9—795. See

SAR with NMR. SI Sawmomab pendetide. 191. 859t

progestins. 785—789 Sex steroids. biosynthesis of. 768—770. 7691 Sibutramtne, 514 Sickling disease, malaria and. 283 Side effects, 9

Sauvagine, $35 Saw palmetto. $03

Sanitoxin, 690

Scahenc. See Lindane Scabicides. 26$ SCF method. 93$ SCH 59884. 244

Schizophrenia, 496—498

aLso Contraceptives

Signal transduction inhibitors, 438—440 Sildenafil. active sites of, 29. 30f Silvadene. See Silver sulfadiazine Silver sulfadiazmne. 279. See also Sulfonamides

indications for, 2701

uiprodrugs. 5. 142. 145, 147—149 water. and, 16 Soluble suppotts. 49. 63 tagging of, 53, 61 Solute, renal reabsorption of. 596—601. 597f -6001 Solation.pltasc coinhmnatorial chemistry, 49, 5111

Suls'ation models, 934 Ssmlvent.acccssible surfaces, 922

Solvents, in molecular dynatnics simulations. 934

Soma. Sic Carisuprodul Somatic cells. trunsgenes in. 94 Somatic nerves, 54$

Somatoliberin.

841

Somatostutin. 841. 845

Somatotrupin. $44

Schraden, 570—571 Schrodinger wave equation. 936—937

Silvbum marianum (milk thistle). 914 Similarity probes. 56. 57t

Sotnatotropin release—inhibiting lactor (SRIF(.

Schwann cell, 679. 6791 Scintigraphy. 458—460. 4581. 4591 Scintillation camera. 458—460. 4581. 4591

Simple proteIns. 831

Somatrem. Ill, 844. %59t Somatropin for injection, 844, (1591 Sonata. See Zaleplon Sorbic acid. 230

Scintillation proximity assay, in highthroughput screening. 54. 541 Scopolamine, 574. 577—578

Scopolamine hydrobromide. 578 Screening. Sec tal.w Computer-assisted drug design of antineoplastic agents. 392—394. 3931 automated. I

biotechnology in. 170—172. 1731 heterologous expression and. 17(1—172. 1701 high-throughput. 26—27, 40. 401. 43, 53—54. 541. 944

human-tumor.colony_forming assay for. 394 madam. 1—2 reporter genes in. 171—172

virtual (in silica). 54—55, 56, 419. 919 senogralt models for. 394 Scurvy, 898 Search query, database, 56 Sehatrol. Sec Flutamide Secobarbital. metabolism of. 76. 77, SI Secobarbital sodium. 494t. 495 Scconal. See Secobarbital sodium Secondary mass spectrumetry. 52 Second messengers. 171, 172, 552 Secretin. 854 Sectral. Si's' Acebutolot Sedatives. See Anttiolytics. hypnotics, and sedatives

Seizures. 503—504 Seldane. See Terfenadine Selective estrogeti receptor modulators (SERMs). 28—29. 291. 781—782. 7811 agonistlantagonisl nctions of. 29 Selective scrotonin reuptake inhibitors. 5 18—520

Selective toxicity. 217 Self consistent field (SCF) method. 938 Self-renewal, 177 Semilente insulin. 851t, 852, 8521 Sempres. See Acrivasune Senapax. Chimeric. See Daclizumab Sernx. See Oxazepam Serentil. See Mesoridazine besylate Serevent. Sec Salmeterol Scromycin. See Cycloserine

Seroquel..See Quetiapine Serosal immunity. 200 Serpasil. See Reserpine Serpins. 665 Sertniline. 519 Serum. 857

Simvastatin. 663 Sinequan. See Doxepin hydrochloride Single photon emission computed tomography 458—460. 4601 S isomer. 35—36. 371 Sisomicin sulfate. 341

$.Sitosterol.

661

Skin infections, fungal. 231, 23lt topical agents for. 233—235 Slater determinant. 937 Slater type functions, 937 Sleeping sickness, 26(1 Sleep-promoting agents. 488 Slow-reacting substances of anaphylaxis (SSRAs), 820 Smallpox vaccine, 21)9 Smoking, drug metabolism and, 131 Snake vcnoms, 835 Sodium, renal reabsorption of, 5961—6001. 597—601 Sodium 4-aminosaticylate, 256—257 Sodium antimony gluconate. 263—264

Sodium uscorbate. 899 Sodium benzoatc, 229 Sodium caprylate. 233 Sodium equilenin sulfate, structure of. 777f Sodium estrone sulfate, structure oF, 7771 Sodium iodide 1131,444,445 Sodium iodine capsules, 469 Sodium iodine oral sotutionlcapsulc. 469 Sodium ion channels. 681, 682—683. 6821. 5cr also Ion channels Sodium nitrite. See Nitrovasodilators Sodium nitroprusside, 654 Sodium PAS. 256—257 Sodium phosphate P 32. 444. 445 Sodium-potassium pump. 682—683, 6821 Sodium prupissnate. 229 Sodium salicylate, 755 Sodium stihogluconate. 263—264 Sodium Sulamyd. See Sulfacetamide sodiunt Sodium sultacetatnide. indications for. 270t Sodium thiosalicylate. 755 Soft drugs. 142 Solanacca spp., 910 Solanaceous alkaloids and analogues. 574—579 Soletene. Sri' Solid.phase synthesis, combinatorial. 46—49.

46f Solid supports. 49. 63 tagging of, 52—53. 521. 52t. 61

Solubility lipid. S and. 17

$45

Sorbitrate. Sec Isosorbide dinitrate. dilated Sonatane. See Acitretin Sotalol, 543. 5441, 642 South American sleeping sickness. 260 Sparfioxacin. 248, 252 Sparine. Sec Proma.sine Spatial amlys. microchip, in combinatorial synthesis. 44. 4Sf. 62 Spatially addressable synthesis. 27 Species differences, in drug ntetabulism. 128—129

Specific immune globulin, 21)7 SPEC'F (single photon emission computed tomogniphy. 458-460, 4601 Sprctazole. See Econazole nitrate Spectinomycin. 335, 341 Spectrobid. See Bacamptcilltn Spectrophotometry, in combinatorial cbeitiisu SI

Spermatogenesis. regulation iii. 774. 7741 Spinal anesthesia. 687. See alum Local anesthetics

Spints. 219 Spironol;mctone. 6l6—6t7. 6161, 6211. 815 extrurenal activity of. 619

Spirunolactonc.hydrochtorothiazide, 620 Split-and-mix synthesis, 43, 44f. 62 Split-level basis sets. 938 Sporanox. See Itraconazole SQ.29548. 8241 Squalene cpoxidasc. 238—239. 2391 SRSAs. 820 Stodol. See Butorphanol lartrate Stanozolol. 7991. 801

Staphcilhin. Si's' Methicillin sodium Starlix. See Nateglinide StAR protein, 768 Stathmokincsis, 427 Statistical methods, in drug design. Staurosporlne. 438

17—26

Stavudine. 381 Steepest descent approach. 930 Stem cells, 177. 1781. 197. l98f Stereochemistry

of drug metabolism.

132—134

of drug—recepror interactIons, 31—34 Stcreoisomeis. biological activity of. 35—37. 351. 361 Stereoselectivity. 35. 103 product. 132—133

substrate,

132

index

Stcnlants, 218—223. 218!

classification of, 218. 21%t elicetivenecs of. evaluation of. 219 improper use cr1, 219

phenol cnelficient for. 221 Sterile capreomycin sulfate. 259 Stenk carticotropin .'.rnc ltydrcmide suspension.

Succinate esters, as prodrugs. 147—149, 1491 Succirtimides. 505—51)6

metabolism of. 109 Succinylclioline chloride. 593—595 Sucorrtrin. See Succinylcholine chloride Sucralfate. 726—727 Sudafed. Set' L.( l-Pseudoephcdrine

formulations of. 275—279

half-life of, 276t indications for. 269. 2701 for intestittal disorders. 279 isonizatlon of, 272—274 mechanism of action of. 270—271. 271 f—273f

androgens. 797—803

Sufentunil citrate, 749 Sulur. See Nisoldipine Salbactam. 315. 316 Sulbactam.amprcillin. 316 Sulconazole nitrate. 242 Sulfacetamide. 276. Sec also Sulfonamides Sallacetumide sodium. 278. See also Sulfonamides

metabolism of. 122. 1231. 269. 274—275 microbial resistance to, 275 mixed. 277—278 nomenclature for. 269. 2711' nonahsorbable. 278—279 nonalanine. 269 oral. 269 values for. 269—270. 274. 274t

us angiogenesis (ultibitors. 447 biosynesis of. 768—770. 7691

Sulfachloropyridaz.ine. 276, See al.crt Sulfonamides

contraCeptives. 789—797 endogenous cofliCosteroidc. 81)3—815 estrogen.. 775 —785

Sulfadiazine, 276t. 277. See also Sulfonamides Sulfadiusine sodium. 277. See also Sulfonamides Sulfadoxino. 276t

prodrug forms of. 269. 279 protein binding of. 274. 275 side effects of, 275 spectrum of action of. 271 —272 structure—activity relationships for. 275 structure of. 271f

842—843. 842t

Stcrilc sasopressin tannate oil suspension. 846t. 847 Steriliration, 2181 Steroid(s). 767—815 adrenal. 803—815

onabolic androgenic. See Androgen(s)

metabolism of. 106. 114 nomenclature for. 767—768, 767f. 7681 numbering of. 767. 7671 overview of, 767—76* pharmacokinetics of. modifications of. 770. 77 If proctrug forms of. 158, 1591. 770. 7711 piugestins. 785—789

properties of. 770. 770t solubility of. 770. 770t stereochemistry of. 767—768. 7671. 7681 Stemidal estrogens, 776. 7771—7781

Steroid hormones. pyridoxinc and. 893—894 Stemidogenic acute regulator)' (StAR1 protein, 768

Steroid receptor complexes. structure of. 773 Steroid receptors, 77(1—773. 7721

structure of. 772. 7721 types of, 773 Stilbenc. metabolism of. 77 Stimate. See Devmopressin acetate Stimulants, 510—522

Stochastic simulations, 935 Stomach. See under Gastrointestinal Stovaine. See Ainylocaine Small. See Idoxundine STP. metabolism of. 91

Strain differences, in drug metabolism. 128— 129

Stniub reaction. 735 Srreprase. Sce Streptokinnue Sueptokinase. 839—840 Streptomycin

cntltubcrculous activity of, 254 discovery of. 299. 334—335 Saeptomycin sulfate. 337—338 Slreptonivicin. 361—362 Streplorocin. 420. 424 Strontium 89 chloride. 444. 445 Structure—actisity relationship. 19—23. 38—39. See also QSAR studies and .cpeeiJk

drugs

indk—.itions for. 2701

Sulfudoxine.pyritttedtamine. 277—278, 2891—29 If, 290—292. 296t. Set' also

Sulfonamides Sulfalene. indications for. 2701 Sulfometbazinc, 271f. 276. See n/co Sulfonamides metabolism of. 122. 1231 also Sulfamethizole. 275—276. 276t. Sulfonamides Sulfumetltoxazole. 276t. 277, Sec also Sulfottantides metabolism of. 122. I 231 Sulfumethovazole and trimethoprim. See Trimedioprim-sulfantclhoxaeole Sullamidochrysodine. metabolism of. 107

5-Sullamoyl.24-3-aminobcnzoic acid dcnvatives. 610—613 Salfamylon. See Mafenide acetate Sulfanilamide. 269. 27 If. See also Sulfonamides antituberculur activiry of, 254 metabolism of, 122. 123f Sal fanilamides, 269 crystalluria and, 274

renal toxicity of, 274 Sulfapyridine. 277. See alst, Sulfonamides metabolism of. 122, l23f Sulfasalazine. 279. See also Sulfonamides azo cleavage in. ISO. 1511 metabolism of. 107—1118

Sulfate cyclodt,strins. 447 Sulfates, conjugation of. 1141. 115—116 Sulfarecin, 334 Sulfcnta. Ste Suleutanil citrate Sulftnpyrazone. metabolism of. 114 Sulfisoxazole. 276. 276t. See a/co Sulfonamides metabolism of, 122. 1231 Sullisoxaeole acetyl. 276. See also Sulfonattuides

Srnjclure.based drug design. 55. 939—944 Stypven. See Snake venoms

Sulftooxazole diolamine. 276, 278. See also Sulfonamides

Subcutaneous injection, drug distnhution and.

Sulfonamides. 268—280 absorbable intermediate-acting. 276t absorbable short-acting. 276t

41. 5—6

Subcutaneous mycosis. 231 Sublimare. See Fentanyl citrate Substance P. 857 Sabstitnenis librunes cr1. 26—27

selection of. 22—23. 23t Substrate stcreoselectiviry. 132 Subtractive deconvolution. in combinatcmnul chemistry. 50

anillne.substituted. 269 br bunts, 278—279 classification of, 269 discovery and development of, 269 distribution of. 274—275 excretion of. 274. 275

987

topical, 269. 2711—279

toxicity of. 122. 274. 275 Sulfones, 279—280 Solfonylureas. 668—670

metabolism of. 94 Sulforidazine, metabolism of. 99, 10(1 Sulfur mustard, 394 Sulindac. 758 active metabolites of. I 35t

metabolism of, 108, 143. l44f prodrug l'orm of. 143. 144f Sunykect, Chimenc. See Basiliximab Supeocntical fluid chromutography, in combinatorial chemistry, SI Sttpcrparamagnetic substances. 476 Suprane. See Desflutane Supras. See Cetixime Suprostonc. 8251 Suramin sodium as antineoplastic agent. 430. 447 us aniiparusitic agent. 264 Surfactants. carionic. 224—227 Surgicoti. See I'lexachlorophene Surgifoam. See Gelatin sponge

Suritul Sudiutn. See Tltiamylal sodium Surmontil. See Trimipramine maleate Sustivu. See Efavirene Sutilains. 839 Symmetrel. See Amantadine Sympathetic ganglia. stimulation of. 586—587 Sympathetic nervous system. 548 Syrrtpatholytics. 524 Sympadtomimetic agents. 510. 524. 5311—539. 548 central. 510, 512—514. 5121 direct-acting. 530—532 a.ctdrenergic receptor agonists. 532—535 receptor agonisr%. 536—537 drug products, 532—539 receptor agonist.s. dual a-and 535

steriroselcetivity of. 530. 532 structure—activity relationships for, 530—532. 53(11

indirect-acting. 537—538 mived-uctimu. 538—539 Syn2869. 245 Synapse. 680, 6801. 683 Synaptic cleft. 680. 6801 Synaptic knob. 679. 6791

folnte coen,.yrnes and. 270—271. 2711—2731

Syneicid. See Quinuprislin.dalfopristin Synnematin N. 318—319 Synterrin. See Rolitetracyclinc

bolate reduciase inhibitors and. 275

Synthnlin. 66)1

988

lndc.v

antibacterial agents. 247—252 Sycttlcrtcid St', l.evothyrc.cnicce srcdcncci

.Syntccciniccc. Sc,' (lnytcccin uicieclion; Oxtocin nasal MIIU1IO1

Tecnpr.c. Sic Acecacccinophcen TenapilSc'c' l)cetlcylgtccpicccc Tenectephase. 18.1

'1mev, Sic Gccanlacine hydrochloride Tectiptcside. 426—427 Teccccnccicc. Sc',' Atenolicl 'l'ensilccn, Sec lidroplc'cccicuun clc),cride

T Tacarvl. Sic Methdila'cne Tachyphylanus. 59(1

TecctaGel resins, icc c,cnchin,ctccrial cltctcccslry. 49 Temcate. 5cc l)cellcylprcipiccn

Tacrine lcytlrlccltloriile,,S67 Tadal'aftl. active sites iii, 29. 31)1

Tepacccil Sc',' l)iethylprtcpion

Tall's steric parameter l1:,. 21 Tagacciet. See ('icoetidinc 'I'aggiccg mctlc4s. fec c,ctcihcccuc,crial Iihr,crics. 52—53, 521. 52c

ti' I)i,tst'asc rallyucnyecccs. 417 Talwin Sec Pcntae,ccicce Tantbtccor. Set' Hec;cinidc ucetace Tacccoxcien, 433, 436, 7Kt -782, 7KIi agicctist/acctagccitist actions ccl. 29 ctcetabcclcsnc

ci. KS

l'antsulccsin, 54) Tc,cc,i,c'ttccci ,cue,heiciiccrc I Ic, erlew).

Taccdcanl. 763t 'rapacole. Scc MelIt,cccai,cle Tapewtcrccc inleslaticcccs, 264-265 Targtwict 'I'eicccplacciic

largretin Sic Besacictetce I'argretitt gel. Sec Bexarcccene Taetraiine. nce)abolisccc ccl, 1117

Taxis) Sec ('lecccastinc iucnarace

'lax,'). Sec Pactitasel Tascctere. Sic' Dccceta',el Taylor serie'. espaccsnccc, ')25

i'ancrotene. 874- 875 T.widictce. Set' ('eftaiitlicccc s,cclinccc 'ra-,obactacct, 3)5, 316 I'aiohactanc—pcperacil)cn,3 lb 'l'a-c,cr.cc,Sc'c' l'a,arotccte Sic Teclcccetiuccc

"IC.

T cells. 2(W). 21)2— 2)1:!

helper. 21$) 'lea bags, in comlcinac,crial syctllcesis, 4-4. 45). 63

Tecelecckin. Sec Aldesleukcn Tectcccetitcccc aibtincin aggregated. 4(c3 —4(c4

Iechnetitcccc albumin c,clloid iccjecticccc. 464 'l'echnetcum alhucccin injecticcn. 463 Teclcccetiuctc apticiile. 464 Teclcneciucn hicisace injeccccccc. 464 Technetinm dcprectide injectciccc. 464 l'echnetinnc di'.oIeccicc cn)eeciccn. 46-I —4(iS Techccetincn exacccetaiicce injectiiccc, 4(cS Tecltnetiuccc meclronate injeccivctc. 41c5 'l'echnetcucn ntcrtcatide iucjectcocc, 465

Technetium pentetate injection. 466 I radiciplcarncacenlicals. Teclcnetinccc 462 —467 Technetiuccc red )cl,cod cells lanrcchcgtcccs I. 46(c Technetiunc sestacnihc cnjevtcon. 466 Technetium sodium penechnet;cte. 466—467 'technetium sciceccuer iltjecticcn. 467 'l'echnetium sulfur coliccid injecticccc. 467 'l'echneciucci tecrcclivsncin injecticin. 467 Tegatccr. 4)17

Tegisccn. Sic Etretinate 'l'egccpen. Set' Closacillin s,cdiccucc Tegretccl. Sc,' ('arbama'iepiccc Teiclcccmycin Ste 'l'eicoplactin

l'eicicplaccin. 356

'l'elnuivartan. lilY Telicncerase inhibitors, 448, l4()i Tencaril See Tricnepracicce Ianr.,te 'l'ecna,epam, 49! l'emosate 'Sc',' ('hohecascil prccpconate

'l'er;c,ol Sic' Tere,cnancle Teracosin. 54(1—541. 541c 'l'er.ce,csicc hydrccchlccride. 652 Terbinaticce Icvdrccehhccride. 23') 'lerbucahine, 536

Thalassencia. ttcalaria acid, 283

iltalitone, See ('hlnrtltalid,cne Tlcallinnu r.cdiccplcannaccnticals. 472 '11w llermlcydrocatcctahinccn. 521) .522 ncetaholisctc ol, 66. 77, 771 'J'hehaitte. 732. 735. 745 Theohroincne, 511—512. SI It 'l'heophyh line as centritl ccers'ous sys)ecn stintctlant.

511—512. SIlt as diuretic. 618 as ncnscle relaxant. 624 'flteriiidide, Set' Sccdiuctc i,idide 1131

ntelaholisnc cci, 87, 115. 126 Tcrcona,ccle. 243

Tlcermodytuactcic cycle. 935 Tliiabend,c,acle. 265 Ttciambutetce, 742 Thiamine. 885—887

Terfeccadicce, 712—713, 7131, 94S

Thiamine hydrochloride. 886—887

Tercccicual hccttccns, 1c7'), 679) 'terc—.ccnycicc,Sc'c' Oxytdracvcliccc hydrccclclccrcde l'eslac,Sc'c' l'estcclactcccce Tessah,ccc, Sc-i' llen,ccnaca)e

'l'tciamiuc ntccccucnitrate, 887 'l'hiacccvlal. ncetahccliscc, ci)'. 81 Thc&crccylal siiditcnt. 487. 487t Thca,ide/chiaaide-like dinretics. 6)15—6111. (cWct. 6) Itt, 6071. 6(18!. Sc,' ,iLc'c' Diuretics

Testolactccne, 436. 783, 784), 785 as anccneicplastic. 434 'l'estcislerccne

hcological activity icE. 797. 798! hivcsvuthesis ol, 76')I, 77)). 7741. 775. 797

adverse effects ot, (illS--tOY drug cnceraetiiitcs with, 609

cccnsec'si,ccc olin estradiol, 783, 7831

tndicarccms Icir, 609—610 (c07—IitlK, 6081 pharmacokiccetics preparatiocts cci, 619—624)

,ccet,cbohcsnt 'if, 71)7

site actd meclcanisccc of artion id, 608

preparations iii'. 7991. 8)81—8)11

stcluhility oF. 770c structure—activity relaticcnships (icr. 7')8— 799, 798c

'I'estostercinc cycliipentylpriipicinate. stnccture ccl. 7711

'I'esl,cs)erone cs'pitcnate. 7's), K)) I

structure iii, 7711 Testccstercccce enthanate. 799, 8)))

'lest,cster,cne propicinate as amucceophastic. 434

scilubihity ii!, hot Testred Sic' I 7a'Metlcs'Itescccstercccce 'lest sets, selection of. 22—23, 23c, 26—27 i'ctanus toxoid, 21 2t, 214, 215 Tetrac.,ine. 69(1—693. 69!! 2.3.7,8.'l'etncL')clicrcidiben/op-cliox,cc c1'C('l It.

cnetaholism at, it, loll 'l'ctr.ccyclinels).34 I - 349 ehelates i'i.342—343 chectuistrs ti). 341 epiccceriiaticcn of, 342

scniccuce—activity retatitcn.s)cips Icir. 64)5—6))?, 6(811. bUtt

l'hia-,ohittdiones, 671—672 Thcenatccyeimsb3l5. 316—317 Tlcimercisal. 228 Thuciguanine. 40)5. 412 Thicipental

hipophilichy at. 7 icuetahuclism cci, 99

Tlti'cpental sodiucn. $87, 487t 'I'hiciper.,mide. 728—729. 7291 Tlcioridazine, 499—5)14. 499t, 5)12 active ctcetatxclites of, I 35, I 35t tctetah,,lisict of, 99 l'hiotepa. 395. 4112

l'hiotlcivene. 5)81 Thiccuracil. 673—674

'llconeylacnitce hydrochloride. 704. 706 Tlcicra,cine 5cc Chlorpt-vcntaaine 31).QSAR. 23, 38—39 31) structural proteiti database. 939. 9391 Thrcctcthiuc, 664. ((iS, 857

inacccvatccin ccl. 342 cnechanisccc ccl action ccl, 343

Tlcroncbccnuridulcn. 6(iS

micrcchial revistactce to, 343 pK,, values (icr, 342. 342t polar. 345

'l'hrccccchosane A2, 666—667, 820), 8211, 822i

prcxlncg fccrnc tct', 149, 15)11

Tlcrottthcipla.stin. 663, 664, (c(i4t, 664t

l'hymineless dean,, 41)1 Tltycccol. 222 Thyrcccalcic'cnin. 855—856

pricperties id'. 344—,U5. 345t spectra!! ccl activity ccl, 343 —344 sterecx'henctslry cit .3.)!. 342t viniccure- activity relationstcips 6cr, 344—345,

'licyrogect. Si',' 'l'hvrtitropicc alpha Tlcyroglohulin. 857 Thyroid Itorcicones. 673 Thyroid-sticnnlatcng hormone 1TSI-li, 845 ilcyroliherin. 84(1—841

structure cit. 34 1—343. 342t 'l'etr.ccycline

'l'hyricpar Sic l'ttvrvcid-sticcciclatiug hccnn,cne

(TSH(

-l etraethylancnc,cctcnttt bnc,ccide. 588 'l'etr.irthvlatnntoccinccc eIcI,cride. 588 letracttcylauttcctonicccct salts. 588 Tetraettcyltetrapltosphate i'F.F.Pt. 569—57)) Tctr.clcydroc,'atcn:,hcnol (Tl-1('l. 520. 522 mecatxchiscci oh. 66, 77, 771 'l'etr,ulcvdrcil,chic acid. 4183—411), 411(1

l'hyrcctropict. 845 'fltyruccrccpict alpha. 176

Tetcahydoceoline..S33

l'(i. Set' 'l'hiiigtcactinc

'l'iagahitcv. 5117 T1l'colone. 796—797, 7971 Tccar, Se,' 'l'ictcrcclhicc ,lis,cdinm

'II IA Sc',' Tacrine hsdrvcchlciride

Ticarcillcn—clavn)anate,3 Ifi

'l'etriidocccs,ct, 694)

'l'hyrotropin.relea.sing ltormone (TRH I.

840-84! -Thyricvine. 673 accalogtces. developttcent ccl, 94(4—941

Index Tkanillin disodium, 309i, 314. Se,' Oh,, Penicillin(sl TiclicLS,'e Ticlopidine l'iclopudine. (,33—634 Tigemonam. 334 Tikosyn. Sic Doretilide

FiI,tdc. See Nedocismtil sodiunt Timcntin. See CIavulat,ate-tk.arcillin Timolol. 543. 5441 Tinioptic. Ste Timolol Tinactin. Ste Tolnaftule Tinctures, 219 Tines, 231). 23). 2311. 233—235

l'ioconaiole, 242 Tipranavir. 942 Tirapaiansinc. activation of, 153. 1541 Tirofuban, 634 Tissue depots. 7 Tissue plasminogcn activator (tPA). 1114 recombinant. 1114. III.)). 840. $59t Tissue lhromboplastin. 663, (,64. 6641 Tts.'.uc tropism. 371

Tiranidine, 534 Tobramycin sulFate. 340 TOC-039. 333 Tocamide hydtm.hloridc. 640

half-life of.

7

Tocopherols. 879—882. See aixi, Vitant,n relative polencies of. 880. 8811t Toc,,trienols. 879. Set' aLso Vitamin E ToIranil. See Imipr.,mine Tokosimide. 669

Tolazoline, 539 Tolbutamide. 269. 668. 669 metabolism iii. 77. 132 age and. 126 Tolbutantide sodmiTi. 61s8 Tulectin. See Tulmclin Tnlinase.S,s Tola.zun,ide Tolmetln, 7511

metabolism of, 77 Tiili,aftale, 239 Tunocard. Si', Toca,nide hydrochloride Topamax. See Tupir.,mutc Topical anesthesia. 687 See ufco Local anecihetics Topiramute, 507

Topological ,kscriplors, in drug design. 23—24. 24,

Toradol. 5cc Ketorolac tromeihamine Toremilene, 434. 436, 781. 7811. 782—783 Tornulate. Sc,' Bitolterol Torscmide. 620 207. 215 Toxoplasmosis, 260 IPA (tissue plasininogen actisaturl. 1114 recombinant, 184. 1841 Tntcclccc linkers, in cot,,binatorial synthesis. 49

Trjcriu,n. See Atracurium hesylate Tr,,c Tab. See Phenyl salicylate Training set. 25 Tratnadol hydrochloride, 747 Tramcinolonc acctoi;idc, structure of, 7711 Trundolapril. 648 Transcription, 162. 1631. 192. 193 Tranvdcrmal contrucephses. 793t. 794 Trunsducins, 871—872 Trnnsgenics, 94 leans isomers, 3) —32

of acetylclioline. 34—35. 34) Tr.,nxene. Sc,' Clorazepate dipolussium Trunylcypromine sulfate. 515—5)6. 5151 Trastuzutitab, 190 as anhineuplastie, 443

Trjvuse. Ste Sutilains Travatan. See Travoprost

Trusopt. See Dor,olamidc

Travoprost. 82)1 Trazodone. 519—52(1 Trecutor SC Ethionamide Trelstur. See Triploralen pomoate

Tiypanosomia.sis, 260

'l'rcmatode infestations, 265 Tremin. See Trihexyphenidyl hydrochloride Treprostinil. 823 Tretinoin. 873 antineoplastic activity of. 430 Triacetin, 233 Triameinolone. relative activity of. $091 Triameinolone .icelonide, 8091, 814—815, 8)41 Trlumcinolone diacetate. $13 Tnamcinolone hexacetonide. 8)3 Tnamlcrcnc. 617. 620 Tnamtcrene.hydmchlorotl,iaride. 620 Tnazolam. 492 Trichilormethiazide. 605—610. (106t, 608t Trichloroethanol, metabolism of, 112 Trichomonia.si'., 260 Tnclofo,. sodium. 496 Triclos. See Triclofos sodium Tricor. See Fenoftbrale Tn-Cyclen. See Norgeslinsate Tricyclic antidepressants, 5l6—519 tttetabolism of, $7 Tridesiol. See Descinide Tridihcttethyl chloride. 584 Tndtone. See Trimethadione Tn-Esl. See Estriol 'fnetbyletieittelamine. 395 Trilluorothytitidine, 407, 4081 Trifiuproma,.ine hydnichloride. 499, 499t Tnhluridine, 376, 407, 4(181 Triglycerides. 657 Trihexyphenidyl hydrochloride. 584 Triiodothyronine. 673 Trimegcslonc, 7871. 7119 'rriinependine. 736*

Trimcprarmne tartrute. 7l1 Trimetbadione. 505 Trimehhaphan, 588

Trimelbapltan cumphorsulfonate. 58$ Trimelhaphan camsylate. 588. 589 Trilnethoprim, 276t. 279 mechanism or action of. 271 metabolism of, 93, 98, 133 structure of. 9421 Trimethoprim analogues, development at, 94l—942

Trimcthoprim.sulfametltoxatole. 272 indications for. 269. 270t Trimeton. See Pheniramine maleate

989

Trypanocidal agents. 668 Trypsin crystallized. 838, 839t Tryplophan Hopkins-Cole test for, 834 metabolism of. estrogens and. 893 TSPA. See Thiolepu Tuberculosis, 254. 338 drug therapy for. 254—259. See also Anhitubcrcular agents Tuberculosis vaccine, 2)2*, 2)4 Tubocurarine chloride. 590-591 Tubuloglomerular lecdbucL 599 Tumor cells, properties of. 390—394 Tumor'infiltrating lymphocytes. 442 Tumor necrosis factor. 44(3 recombinant, 183, 447 Tusscapine. See Noscapine

2-PAM. prodrug form of. 157—lStl, 1581 TXA2. Set' Thromboxane A2 Tylcnol. See Acetaminophen

Tyrocidin. 299 Tyrocidine. 360 Tyropanoace sodium. 484

Tyrosine. Miller's test for. 834 'l'yrosine hydrunyla.se. 524—525. 5251

Tyruthricin. 359-360 Tyzine. See Tetruhydrozoline

U

U-46619. 8251

UCN-0l. 439 UDPGA. in glucurunidation. 112 UDP'glucumnyltransferases. 112, 1)21 Ugi reaction, four-component, 49, 5(11 Ulcers, peptic. 718—719 Ultiva. See Retnifentanil hydrochloride Ultrtilente insulin, 851t. 852. $521 Ultram. See Tramadol hydrochloride Ultrasound. contrast agents for. 477 Llnasyn. See Ampicillin-sulbactam Undecylenic acid, 233 Unipen. See Nalcillin sodium Uniprost. 825 Unoprostone. 828 Ureas. 506 Urecholine. See Betitanechol chloride Urinary analgesics. 253—254 Urine. sulfanilamide solubilily in. 274 Urised. See Methylene Phenyl salicylate Uritonc. See Melhenamine Urokinase. 840 Urotropin. Sec Methenamine

Trimetrexute. 410—411

Tritnipraminc maleate. 517 Tripelcnnum,nc. 704. 705 metabolism of. 87, 114. 705 Tripclennamine citrate. 705 'rripelcnnutninc Itydrochloride. 705 Triple sulfa. 278. See aix,, Sulfonamides Triprolidine hydrochloride, 709 Triptoralen pamoate. 437 as antineoplastic. 435 Trisenox. See Arsenic trioxide l'risullupynmidines. See aLso Sulfonamides oral suspension. 277 tablets, 277 Trivalent oral polio vaceine. 2)0. 2121 'l'roleandomycin. 353 Tropeines. 676 Tropicamide. 585 Tropinc. 575. 676. 6771 Tnie salol. 755

V i (Chttrton's steric parameter), 21

Vaccittutton, definition of, 207 Vaccine(s), 207 acellular. 207—20%

administration schedule for, 2121. 215—216

bacillus Caltnette-Gudrin. 2)4 u.s antineoplastic. 440. .142

bacterial. 2l2t, 213—215 booster, 2011

chickenpox. 211. 212t cholera. 2121. 214-215 coadministered. 208

definitiott of. 207 diphtheria, 212t. 2)4—215 dosage of. 208 DPT. 212t. 215 lluemophllw. inflttenzae, 2121. 214

990

/ot/it Vectmtrs. cltttimtg, 11m5— (66. 1661. 468

dascoven' uI, 866-867

hepatitis A. 211—213. 21 It hepatitis II. 2 2t. 2(3. 85th. 116th hepatihis 1'. 213 hepatitis E. 213

Vectrttt Set' Mimtoeycline liydrochlonde Vecuntttitmui broittide, 593

luuctttmus ot'. 866

human mmtiuunttdeltcter.cv situ'.. 182—3(11

Venial astue. 519 Vettograptty. 479

Vaccinet s (nutiinut'd#

tttlltieiiiti, 2(8) killed btnaemhaledh. 207 live/attenuated. 2(17 malaria. 283—285 measles. 2111-211. 21 2t meutugococeal pol) saceharide. 215 multiple-dose. 2(18 mulimvalemtt. 208

S'eloset. Sec Cephadritte

Ven Apis Set' (lee veuout'

Vemttstns 835

Venmttlitt, Set' Albuterol

VePestil Sic Etopctsitle Vcrapanttl us atitiarrttytbinic. 1.42 is sasttdilator. 629. 629t Verltittp's titultidititetisittual sterme parattteters.

mumps. 211, 2l2i pcm'tussis. 212.. 213—214

pharmaceutical principle' .8. 248) pneutntmcoccal. 215 polio. 2(41. 21 2t

polysalent. 208 production itt. 2447—2148 recoutbmuant. 186- 187. 187.. 24(8. 21)81 rotavmnis. 213 rubella. 2111. 21 2t

Verluma Kim. See Noktitmomoah tnerpetuan Vermtios, See Mebeudaiole Veiiimteautine, 728-729. 7291 Verstr,ttt. Sec Prucepatit Very- ((((v-density lipoptoteitts. 658—659. 85(1

Vesprin. Sr.' 'lrillttprotmtaiiue ltydrttclmliiride Viagra See Sildeitalil Vihe,tnvccitt. See l)ovyeycline

labeling requtrettteuts for. 866. 866t lipid-soluble. 866- 885 overview ut, 866—867 recommended daily intake iii. 866. ShOt supplemnetttal. indications titr. 86(i scaler-soluble. 885—918) Vitatmmiu A. 867—875

hitueheniical Ittttctiitns ,t(, 87(1

biological activity at. 867 biosynthesis uul. 869-8711 etilite reaction', 55 itlt, 869

crystalline. 869 deficmettcy uI, 8711 delimmititiu mit, 868

dietary sources cit. 868, 868t, 869—870 eneecs of. 870—871 in ft,slt liver oils, 8(m8t, 869

isttttters 01, 868, 868t. 872 tttechuttisns al actittmt itt, 872 mciubuilisttm o1, 86')

uutttberiug system [or. 868

Victtttmtycin, 417 Vidar,tbitte -'cci' Adetitisitte arabmnosmde

pruxlttcms. 872—875

sitmule-tltise, 208 stmtallptis. 2(19 storage tin1 hattdlitmg ot. 2(49 tetattuc. 212t. 214—215 tubercuhicts. 21 2t. 214 vir,tl, 21(9—213. 367—3744 Vtttti,titmt spp. bcmttnberrs' '112

S'ides See Didantisitte Viublastitte sulfate, 425. 41St. 427

retinoie acid receptors and. 872

Vinci alkaliitds, 324 425. 425t. 9(5

structure—activity relationships for. 869

Vimicristtmte sullate, 325, 41St. 427 Vtmtesine. 425, 425t

tosictty of, 8711—871

Vaginal ritig contraceptive des ice. 7'11t. 794 Vagistut See Ttocoua,,tle

Viutirelbine tartrate. 427 Vinrosiditte, 425. 425t Viuyl chloride. tttetabttlisnt itt', 77 Vuititrtmt. See Ultitqttinol

simple. 20$

Vinglycittate. 425. 425t Vimmleiut,sitte, 425, 425t

Valacyclovir hydriicltlt.rtdr. 377 Valdecosib, 76(4. 822—823 Vajeriau, 914—915 Valium

l)itmeepani

Valnthiciu. 416, 423 Valsatlan, 64') Val',tar. See Valnibictu Valtres Set' Valacyclos ir hydtttcltli'ride Vancettase. See Ileelitittetltasotie diprttpiotmate Vauceril Sit' Ilecloutetlvootte tltpriipiouatc Vancitctn Sic Vancontycin Itydnicltloride Vaucoled.St'.' Vauc,tmi.vcitt Vamtcittttyciu. 34 Itt

Vattcitntycitt hydrttctdortde, 355 356 Van der Waals' Iorces.3 I. 34 Van der Waals' sttriace. in tt.otrcttla. tmulelotg. 922. 9221 Vauostde. Sit' Hydrotis beutityl peroxide Vansil. See Ovammtmtiqtttne

Vautiu. Set' ('elpodositne proxetil Vardenal'il u,'tive sites ut . 29, (III Variamycins. 4(7 Varicella vaccine, 241. 21 2t

Vitatttmn

8145

1487

tlelicieticy itt. 891

Viracepi .5.'.' Neliluavir

diemttry ctturces of. K')2

Viral imtl'eetions, Se.' ohiti Viruses htttxi in. 367 cattcer ,tttd. 372 clteutopropltylasis (tie. 372 tosis in. .171 host-virus interactions in, 371 tititoutti/ation (or, 2(8/- 213, 367—3711.5cc

discovery at, 894

alt" Vtteciuebst prtuhtenve. 367 stages all 3744—372

Vieamtttttiiitr. Set' Nesirapitte

Vtrioti, 172

'l'rilluridine Virtual screenIng, 54—55. 56, 63. 919

Viruses See ti/ia Viral itikctitms building of. 372

lmttnmttttmes antI. 893 $t(4

products. 894 pntpenies ttf, 891 —8't4

Vitatnin Be.. 89l896 deficiency at. 895 tctltc acid metulxilisttt ..ttd. 896 897 potdttcts. SQS—891m

properties uti. 894—895 titsicity of, 8115 Vtma,otu Rix.. 894 Vitamin C. 898—1499 Vitatuin 1). 875—879 absturptittu iii. 877

hiolttgteal activity utt . 876 hiosyutttesis iii. 875—876

cleissiflcammt,u t,l, 167, 3681—37(11

deficiency tit, $76 ttietary stutrees it, 877

l)NA. 368t. 37th. 372

eveess all 876—877

oTicogenic. 372 overs-iesv iii, 167 mephicahlttu .1,367, 371. 372 KNA, 139t. 36Km. 371—372

toeiabttlism id. 875

cltar,tcteristtes ol, 367

Visken Set' I'intltilol Vtsttde .cc.' (3dolttvit V stray Set' Ovypheueycliittine hydrochloride Visual purple. 871, 872

Vasttpressimm tzutuate. 8-tot. $47

Vist.al 870 Vitaniitttst, 866—94(2 tlaily values ut. 866. 8661

V-Cillitt Si'.' Penicillin V

Viiamtmimm A., $75

Vilatitimt B,,. 1191 894

ntechanismtt itI actiott ot, 4,22 623. tt2it ntetabvtlisnt itt', 623 623, tt25t Vasopressiti, 845 8.16 Vasopressin iuieetitm. 8-lbt, $47

Vasox> I Si'.' P,letltttsamutne

(,'SP. 872-873 itt visittu. 870. 871—872 Vitttmiu A1. 867, 168

Viiivs Ste Ritlecosib

Vtsn.e Sit' 'fetretltydr.vtolttte Vistou. s ttamttmtm A tnd. 870, 872.873

eycltidesiritt

uttits nil, 86%, 868t

S'iotm.yctmt. 259

Vaccutr St-c Ilepridil ltvdtimchmlortde Vasoaettve intestinal ps'ptttle. 1455 Va'.ocouctrtctitts, mt local anesthesia. 688 Vasrulilators, ('22- 1.31 antianginat. 622—626. See u/tie Nit retva.sititilators antittypertetisive. 1.53 1.54 ant,thrittmtbotic. 1t32—634

Vasuprost See l'rostaglaudiu Vasotee. Ste Ettalupril

stereoeheimtislry of. 868

Vumamin B:. 89(1—1191 Vitamin 887- 1488

Set' Adenttsiue arahinoside

Valprote acid, 51(6 mttetaholisttt tit. St

pros itautitis, 869— 87tt

tissue mt'opismtt at, 371 tutcoatimtg tI. 371

deliciencies al, 866 dieiary reference intuhes t,l, 866, 867t

products. 877—879 potperlics tIll 1175—877

tttsiciiy utt. 876 1177 Vitamtiin I) receptors. 877 therttpcumic uses uI', 1477 Vitamitu F, 879—1112

absi'rpiitiu al, 88(1 881 autiosidaut properties uI, 8811 -XIII deficiency oh. 881 dietary s.tttrees at. 879—812 discosery till 879 tu:tclivatiou uI'. 881) isttltunos ol, 879 —8811 ttteg;tdoses tiE, 881 u,etahttlismtt at'. 881

propetties cut. 88tt

Index African sleeping sicknc'.s. 260 Wes(heimer method, 923 Whitfueld's Ointment, 234 Wilpowr. See Phentermine hydrochloride

relative poicnctes ol. 88(1. 8818 of. 881—882 thcrapcuttc Vitamin G. 890—891 Vilantiti K. 882—1(85

ihsiirpliiin iii. 883 anticoagulant activity of, 665. fi661 dictar) sources ut. 882. t182t discovery ol. 882 Iuiictutms ni, 883 iiictaholism of. 883

VP. I (i..'i'i'i'

Wycillin. St't' Penicillin (3 procaine Wydase. Set' Hyalumnidase (or tnjection

Zan,nlin.St't' Ethi,susimide Zarsixotyn. Sit'

Wytensin, Set' Guanahcne acetate

Zebeta. Si-u' Bisoprolol '/.cfaione. See Crtmeia,ole sodiuuti, Zcmplar. Set' Paricalcitol

x

Zcntel. Ste Alhetidazote Zcphiran.Si't' lIeuw.all.tiniiutn citloriule Zerit. Set' Stavudine Zero modulators. 489

Xaltutatt. Ste Latittiopront Xanax. Ste Alpruaolum Xututhincs, 511—512.51 It Xanthoproteic test, 834 Xcloda. See Capecitahinc Xenobiotics. definition of, 65

Zesiil.Se.' Lisinopril Zcvulin kit. Sit' Ibritumomab IluSetan Zidiuvudine, 379—384)

Xenon r.udiopharmaceutucals. 472

Zikuton, 820

Xigris. Sue Rotrceogin alfa

Zitiucet. See Cefuroxime sodium Zinc caprylale, 233 Zinc propionate, 233 Zinecard. See Dexrtuiuxanc S i'.xinters, 32. 321 Zithrtunuax. Si'.' A,.itbroinycin 7,ocor. Set' Sjnis'asluiin Zolades. Sit' Goserelin Zuloll. See Sertr,iline Zolpidem, 492 Zonegran.Sei' Zsunisainide Zonisamide, 507

Xipamide. 607—6111, 6071, (i09t, 621)

Vumon Sri' Teniposide

Xupenex. Set' Levalhuterol X-ray crystallography, 37—38 X'ray films. 454. 472—473

w

Xylocaine. St'i' Liulocaine hydrochloride

Warfarin active mclatxilitcv iii. 1351 metabolism ul, 10. 105. 32 sites ut action of. 1,61,1 Warlarin potassium, 1,1,7 —Wit) Warfann sodium. 61u7 Waler, a'. atliphaleric sutistance. II soliuhility. pK, and. I 6 Waler-soluble vitamins, 81(5—'XK).S Vitamin(s) Water solvent models. 934 Watson-Crick DNA r,ioulel, 921t Weicliol Set' Colesevelant Welibutrin. See Buipropion Wellferuin.S,'u' Inlerteron I

Xylometai.uulune. 537

454

V YA-56, 417 Yeast infections. Set' Eungul infections See Induuquinol

Jut

Zalcitahine, 380—381

Winstruit. Set' Stanorolot Wyumycin. See Erythromycin steurute

products. 884—1(85

iclaliotiships 1(82—883 therapeutic usc'. iii, 883 Vitantiti K1, 884-885 Vitamiti 882 Vitamin K. 81(2, 1(85 Vitamin Ka. 882 Vitamin K inhibitor'.. 1,1,7 Vi'. actil. See Prutriplyliue li)drui.liloride VM-26 Set' Voltarcn.S,'i' l)iclotcn.ic 'odium Vorici,naiok. 244— 245

Zaditor. See Kecotifen tumaraw ophthalmic solution Zaleplon. 41)2.493 Zanafles. See Ti,aniditte Zanuisar.Si'e Strepto,.ocin Zantac. See Ranitidine

Wine spini. St't' Alcohol

Yoltimbinc, 541 See Niclosamide Yutuupar. See Ritiidnne

zorhaniycin, 4(7 7.orbnnamycins, '1(7

Zosyn. Sit' Taeohactam.piperacillin Zovirax. See Acycliivir Zytlo. See Zuteuton Zymiigcn granules, 838 Zyittogen'., 1(37

z 7,actanc Citrate. See Ethoheptarinc Zactirin. Set' Ethohepluzine

991

Zyprexa.S.'e Olaticapine Zyrtec. Si'.' ('ettnzinc Zyvuis. Set' l,inezisl(d