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WILSON AND GISVOLD'S

Textbook of Organic Medicinal


and Pharmaceutical Chemistry
Tenth Edition

EDI TED BY

Jaime N. Delgado, Ph.D.


Division of Medicinal Chemistry. College of Pharmacy
University of Texas at Austin, Austin, Texas
AND

William A. Remers, Ph.D.


Department of Pharmacology and Toxicology. College of Pharmacy
University of Arizona, Tucson, Arizona

24 Contributors

Lippincott - Raven
P U B L I S H E R S

P h i l a d e l p h i a S e w Y o r k
CONTENTS

CONTRIBUTORS xiii

PREFACE xv

CHAPTER 1
Introduction 1
Jaime N. Delgado and William A. Remers

CHAPTER 2
Physicochemical Properties in Relation to Biological Action 3
John H. Block

Overview 3
Drug Distribution 3
Acid-Base Properties 10
Statistical Prediction of Pharmacological Activity 18
Combinatorial Chemistry 25
Molecular Modeling (Computer-Aided Drug Design) 26

CHAPTER 3
Metabolic Changes of Drugs and Related Organic Compounds 43
Lawrence K. Low

General Pathways of Drug Metabolism 43


Sites of Drug Biotransformation 45
Role of Cytochrome P-450 Monoxygenases in Oxidative Biotransformations 45
Oxidative Reactions 48
Reductive Reactions 81
Hydrolytic Reactions 89
Phase II, or Conjugation. Reactions 91
Factors Affecting Drug Metabolism 109

CHAPTER 4
Drug Latentiation and Prodrugs 123
Forrest T. Smith and C. Randall Clark

History 123
Basic Concepts 123
VI CONTENTS

Prodrugs of Functional Groups 125


Bioprecursor Prodrugs 132
Chemical Delivery Systems 134

CHAPTER 5
Biotechnology and Drug Discovery 139
John W. Regan

Cloning DNA 139


Expression of Cloned DNA 142
Manipulation of DNA Sequence Information 143
New Biological Targets for Drug Development 144
Novel Drug-Screening Strategies 145
Novel Biological Agents 147
Antibodies 148
Antisense Oligonucleotide Therapy 148
Gene Therapy 149
Products 150

CHAPTER 6
Fundamentals of Immunology and Immunizing Biologicals
(Vaccines and Toxoids) 153
John M. Beale

Disease Prevention: An Historical Perspective 153


Fundamental Immunological Nomenclature 154
The Chemical Nature of an Antigen 155
Fundamental Immunological Concepts 156
Antibody Types and Reactions 162
Immunobiologicals (Vaccines and Toxoids) 164

CHAPTER 7
Anti-Infective Agents 173
Arnold R Martin

Local Anti-Infective Agents 173


Alcohols and Related Compounds 174
Phenols and Their Derivatives 176
Oxidizing Agents 178
Halogen-Containing Compounds 178
Chlorine-Containing Compounds 179
Cationic Surfactants 180
Dyes 181
Mercury Compounds 182
Preservatives 183
Antifungul Agents 185
Antifungal Antibiotics 193
Synthetic Antibacterial Agents 196
Antitubercular Agents 204
Antitubercular Antibiotics 208
CONTENTS VII

Antiprotozoal Agents 210


Anthelmintics 216
Antiscabious and Antipedicular Agents 219

CHAPTER 8
Sulfonamides, Sulfones, and Folate Reductase Inhibitors with
Antibacterial Action 223
Dwight S. Fullerton

Sulfonamides and Folate Reductase Inhibitors 223


Well-Absorbed, Short-, and Intermediate-Acting Sulfonamides 229
Sulfonamides for Ophthalmic Infections 231
Sulfonamides for Burn Therapy 231
Sulfonamides for Intestinal Infections, Ulcerative Colitis, or Reduction of Bowel
Flora 231
Folate Reductase Inhibitors 232
Sulfones 232

CHAPTER 9
Antimalarials 235
Dwight S. Fullerton

Etiology 235
History 237
Modern Malaria Chemotherapy: An Overview 240
Development of Malaria Vaccines: Promising or a Failed Promise? 240
Quinolines and Analogues 241
Cinchona Alkaloids 244
7-Chloro-4-Aminoquinolines 246
8-Aminoquinolines 247
9-Aminoacridines 248
Mefloquine 248
Tetrahydrofolate Synthesis Inhibitors 248
Diaminopyrimidines 249
Biguanides and Dihydrotriazines 250
Sulfonamides 251
Sulfones 251
Other Antimalarials 251

CHAPTER 10
Antibacterial Antibiotics 253
Arnold R Martin

Historical Background 253


Current Status 253
/3-Lactam Antibiotics 255
The Aminoglycosides 291
The Tetracyclines 299
The Mac roc I ides 307
The Lincomyeins 312
The Polypeptides 314
VIII CONTENTS

CHAPTER 1 1
Antiviral Agents 327
Arnold R Martin

Properties of Viruses 327


Viral Classification 327
Prevention of Viral Infection by Chemoprophylaxis 327
Nucleoside Antimetabolites 331
Agents Under Development for HIV Infection 337

CHAPTER 12
Antineoplastic Agents 343
William A. Remers

Tumor Cell Properties 343


Alkylating Agents 347
Antimetabolites 356
Antibiotics 368
Plant Products 379
Miscellaneous Compounds 382
Hormones 388
Immunotherapy 391
Future Antineoplastic Agents 393

CHAPTER 13
Agents for Diagnostic Imaging 403
Jack N. Hall and Tim B. Hunter

Introduction to Radiation 403


Biological Effects of Radiation 406
Radionuclides and Radiopharmaceuticals for Organ Imaging 407
Radionuclide Production 408
Technetium Radiochemistry 411
Fluorine Radiochemistry 418
Gallium Radiochemistry 418
Iodine Radiochemistry 419
Indium Radiochemistry 420
Thallium Radiochemistry 422
Xenon Radiochemistry 423
Radiologic Contrast Agents 423
Paramagnetic Compounds 426
Radiologic Procedures 427

CHAPTER 14
Central Nervous System Depressants 435
Eugene / Isaacson

Some Mechanisms of Action: Anesthetics, Sedative-Hypnotics, Anxiolytics, and


Anticonvulsants 435
General Anesthetics 436
Anxiolytic, Sedative, and Hypnotic Agents 439
CONTENTS | IX

Central Nervous System Depressants with Skeletal Muscle Relaxant Properties 448
Antipsychotics 449
Anticonvulsant or Antiepileptic Drugs 456

CHAPTER 15
Central Nervous System Stimulants 463
Eugene I. Isaacson

Analeptics 463
Methylxanthines 464
Central Sympathomimetic Agents (Psychomotor Stimulants) 465
Monamine Oxidase Inhibitors 469
Tricyclic (and Mechanistically Related) Antidepressant Compounds 471
Psychedelics 474

CHAPTER 16
Adrenergic Agents 479
Rodney L. Johnson

Adrenergic Neurotransmitters 479


Adrenergic Receptors 482
Drugs Affecting Adrenergic Neurotransmission 484
Sympathomimetic Agents 485
Adrenergic Receptor Antagonists 494

CHAPTER 17
Cholinergic Drugs and Related Agents 505
George H. Cocolas

Cholinergic Receptors 506


Cholinergic Neurochemistry 510
Cholinergic Agonists 511
Cholinergic Receptor Antagonists 515
Cholinergic Blocking Agents 527
Parasympathetic Postganglionic Blocking Agents 529
Solanaceous Alkaloids and Analogues 530
Synthetic Cholinergic Blocking Agents 535
Ganglionic Blocking Agents 542
Neuromuscular Blocking Agents 545

CHAPTER 18
Diuretics 553
Daniel A Koechei

Anatomy and Physiology of the Nephron 553


Function 553
Introduction to the Diuretics 559
Site I Diuretics: Carbonic Anhydrase Inhibitors 561
Site 3 Diuretics: Thiazide and Thia/ide-like Diuretics 563
Site 2 Diuretics: High-Ceiling or Loop Diuretics 569
Site 4 Diuretics: Potassium-Sparing Diuretics 575
Miscellaneous Diuretics 579
Summary 579
X I CONTENTS

CHAPTER 19
Cardiovascular Agents 583
George H. Cocolas

Antianginal Agents and Vasodilators 583


Antiarrhythmic Drugs 594
Antihypertensive Agents 603
Antihyperlipidemic Agents 614
Anticoagulants 620
Synthetic Hypoglycemic Agents 625
Thyroid Hormones 627
Antithyroid Drugs 628

CHAPTER 20
Local Anesthetic Agents 631
Gareth Thomas and David E. Thurston

Historical Development 631


Nervous System 634
Mechanism of Action 640
Administration 642
Factors Influencing the Effectiveness of the Anesthetic Action 642
Rate of Onset and Duration of Anesthesia 644
Secondary Pharmacological Action 644
Structure-Action 645
Lexicon of Local Anesthetics 648

CHAPTER 21
Histamine and Antihistaminic Agents 657
Thomas N. Riley and Jack DeRuiter

Histamine 657
Histamine Life Cycle 657
Histamine H,-Receptor Antagonists: Antihistiminic Agents 661
Inhibition of Histamine Release 675
Histamine H2-Receptor Antagonists 676
Histamine H3-Receptor Ligands 683

CHAPTER 22
Analgesic Agents 687
Robert E Willette

Morphine and Related Compounds 687


Antitussive Agents 709
Anti-Inflammatory Analgesics 711

CHAPTER 23
Steroids and Therapeutically Related Compounds 727
Dwight S Fullerton

Steroid Receptors 727


Steroid Nomenclature, Stereochemistry, and Numbering 731
CONTENTS XI

Steroid Biosynthesis 735


Chemical and Physical Properties of Steroids 736
Changes to Modify Pharmacokinetic Properties of Steroids 736
Gonadotropins 736
Sex Hormones 741
Estrogens 741
Antiestrogens and Related Drugs 750
Progestins 752
Chemical Contraceptive Agents 755
Androgens and Anabolic Agents 764
Adrenal Cortex Hormones 770
Cardiac Steroids and Related Inotropic Drugs 781
Steroids with Other Activities 794
Commercial Production of Steroids 795

CHAPTER 24
Prostaglandins, Leukotrienes, and Other Eicosanoids 803
Thomas J. Holmes, Jr

History of Discovery 803


Eicosanoid Biosynthesis 803
Drug Action Mediated by Eicosanoids 807
Design of Eicosanoid Drugs 808
Eicosanoids in Clinical Development for Human Treatment 810

CHAPTER 25
Carbohydrates 813
Vilas A, Prabhu and Jaime N Delgado

Classification 813
Biosynthesis 816
Stereochemical Considerations 816
Interrelationships with Lipids and Proteins 817
Sugar Alcohols 818
Sugars 819
Starch and Derivatives 822
Cellulose and Derivatives 822
Heparin 825
Glycosides 828

CHAPTER 26
Amino Acids, Proteins, Enzymes, and Peptide Hormones 831
Jaime N Deigjoo J'ia i' JS A P\-i"\.

Amino Acids 831


Protein Hydrolysates 835
Amino Acid Solutions 835
Protein and Protein-like Compounds 836
Enzymes 841
Hormones 846
XII CONTENTS

Blood Proteins 864


The Impact of Biotechnology on the Development and Commercial Production of
Proteins and Peptides as Pharmaceutical Products 865
Biotechnology-Derived Pharmaceutical Products 868

CHAPTER 27
Vitamins and Related Compounds 875
Gustavo R. Ortega and Jaime N. Delgado

Lipid-Soluble Vitamins 875


Water-Soluble Vitamins 894
Miscellaneous Considerations 910

APPENDIX
pKas of Drugs and Reference Compounds 915

INDEX 923