Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry

Wilson and Gisvold\'s Textbook of Organic Medicinal and Pharmaceutical Chemistry, Twelfth Edition......Page 1
Title Page......Page 3
Copyright......Page 4
Dedication......Page 5
Students......Page 6
ACKNOWLEDGMENTS......Page 7
CONTRIBUTORS......Page 8
CONTENTS......Page 9
CHAPTER 1: Introduction......Page 13
Oral Administration......Page 15
Parenteral Administration......Page 17
Protein Binding......Page 18
Drug Metabolism......Page 19
The Receptor......Page 20
Summary......Page 23
Acid Strength......Page 24
Percent Ionization......Page 26
Drug Distribution and pKa......Page 28
Statistical Prediction of Pharmacological Activity......Page 29
Partition Coefficient......Page 30
Other Physicochemical and Descriptor Parameters......Page 32
Topological Descriptors......Page 34
Classification Methods......Page 35
Has QSAR Been Successful?......Page 36
Forces Involved with Drug–Receptor Interactions......Page 37
Conformational Flexibility and Multiple Modes of Action......Page 41
Optical Isomerism and Biological Activity......Page 42
Calculated Conformations......Page 44
Three-Dimensional Quantitative Structure–Activity Relationships......Page 48
Database Searching and Mining......Page 49
Isosterism......Page 51
SELECTED WEB PAGES......Page 52
SELECTED READING......Page 53
GENERAL PATHWAYS OF DRUG METABOLISM......Page 55
ROLE OF CYTOCHROME P450 MONOOXYGENASES IN OXIDATIVE BIOTRANSFORMATIONS......Page 57
Oxidation of Aromatic Moieties......Page 59
Oxidation of Olefins......Page 64
Oxidation at Allylic Carbon Atoms......Page 67
Oxidation at Carbon Atoms α to Carbonyls and Imines......Page 70
Oxidation at Aliphatic and Alicyclic Carbon Atoms......Page 71
Oxidation Involving Carbon–Heteroatom Systems......Page 72
Oxidation of Alcohols and Aldehydes......Page 88
REDUCTIVE REACTIONS......Page 90
Reduction of Aldehyde and Ketone Carbonyls......Page 92
Reduction of Nitro and Azo Compounds......Page 95
Miscellaneous Reductions......Page 96
Miscellaneous Hydrolytic Reactions......Page 98
Miscellaneous Bioactivation of Prodrugs......Page 99
PHASE II OR CONJUGATION REACTIONS......Page 100
Glucuronic Acid Conjugation......Page 101
Sulfate Conjugation......Page 103
Conjugation with Glycine, Glutamine, and Other Amino Acids......Page 105
GSH or Mercapturic Acid Conjugates......Page 106
Acetylation......Page 109
Methylation......Page 114
Species and Strain Differences......Page 116
Hereditary or Genetic Factors......Page 117
Enzyme Induction......Page 118
Stereochemical Aspects of Drug Metabolism......Page 120
Pharmacologically Active Metabolites......Page 123
REVIEW QUESTIONS......Page 124
REFERENCES......Page 125
SELECTED READING......Page 129
BIOTECHNOLOGY AND NEW DRUG DEVELOPMENT......Page 131
THE BIOTECHNOLOGY OF RECOMBINANT DNA......Page 133
Recombinant DNA Technology......Page 135
The Vector......Page 136
Homology-Based Cloning......Page 138
MANIPULATION OF DNA SEQUENCE INFORMATION......Page 139
NEW BIOLOGICAL TARGETS FOR DRUG DEVELOPMENT......Page 140
NOVEL DRUG-SCREENING STRATEGIES......Page 141
PHARMACEUTICS OF RECOMBINANT DNA-PRODUCED AGENTS......Page 143
Physical Instability of Proteins......Page 144
Hormones......Page 146
Cytokines......Page 148
Interferons......Page 150
Aldesleukin......Page 153
Blood-Clotting Factors......Page 154
Other Enzymes......Page 156
Products......Page 157
Hybridoma (Monoclonal Antibody) Techniques......Page 158
Monoclonal Antibody Drugs......Page 159
Monoclonal Antibody Radionuclide Test Kits......Page 161
Unraveling the Genomic Code to Determine Structure–Function Relationships: Bioinformatics......Page 162
DNA Microarrays......Page 163
ANTISENSE TECHNOLOGY......Page 164
REFERENCES......Page 165
Phagocytes......Page 168
Macrophages and Monocytes......Page 169
Innate Immunity......Page 171
Acquired (Adaptive) Immunity......Page 173
Definitions of Immunobiologicals......Page 177
Immunobiologicals (Vaccines and Toxoids)......Page 178
Viral Vaccines......Page 180
Bacterial Vaccines......Page 184
Toxoids......Page 185
NEW VACCINE TECHNOLOGIES: ADJUVANT TECHNOLOGY......Page 186
NEW VACCINE TECHNOLOGIES: NUCLEIC ACID VACCINES......Page 189
REFERENCES......Page 190
CHAPTER OVERVIEW......Page 191
EVALUATION OF THE EFFECTIVENESS OF A STERILANT......Page 192
ALCOHOLS AND RELATED COMPOUNDS......Page 193
Aldehydes......Page 194
PHENOLS AND THEIR DERIVATIVES......Page 195
HALOGEN-CONTAINING COMPOUNDS......Page 197
CATIONIC SURFACTANTS......Page 198
DYES......Page 200
MERCURY COMPOUNDS (MERCURIALS)......Page 201
Other Preservatives......Page 202
General Introduction to Fungi: Medical Mycology......Page 203
Cutaneous Infections (Dermatophytoses)......Page 204
Tissue Reactions of Fungal Disease......Page 205
Topical Agents for Dermatophytoses......Page 206
Antifungal Antibiotics......Page 208
Allylamines and Related Compounds......Page 211
Azole Antifungal Agents......Page 212
Quinolones......Page 218
Nitrofurans......Page 225
Antitubercular Agents......Page 226
Antitubercular Antibiotics......Page 230
ANTIPROTOZOAL AGENTS......Page 232
ANTHELMINTICS......Page 236
ANTISCABIOUS AND ANTIPEDICULAR AGENTS......Page 239
ANTIBACTERIAL SULFONAMIDES......Page 240
Mechanism of Action of the Sulfonamides......Page 242
Ionization of Sulfonamides......Page 244
Metabolism, Protein Binding, and Distribution......Page 246
Structure–Activity Relationships......Page 247
Mixed Sulfonamides......Page 249
Sulfonamides for Intestinal Infections, Ulcerative Colitis, or Reduction of Bowel Flora......Page 250
SULFONES......Page 251
REFERENCES......Page 252
SELECTED READING......Page 253
Malaria......Page 254
Controlling the Vector, the Anopheles Mosquito......Page 256
CINCHONA ALKALOIDS......Page 257
4-Aminoquinolines......Page 260
8-Aminoquinolines......Page 262
Polycyclic Antimalarial Drugs......Page 263
Fixed Combinations......Page 265
Future Trends......Page 267
REVIEW QUESTIONS......Page 268
SELECTED READING......Page 269
HISTORICAL BACKGROUND......Page 270
MECHANISMS OF ACTION......Page 271
β-LACTAM ANTIBIOTICS......Page 272
Nomenclature......Page 273
Stereochemistry......Page 274
Chemical Degradation......Page 275
Bacterial Resistance......Page 277
Extended-Spectrum Penicillins......Page 279
Allergy to Penicillins......Page 280
Products......Page 281
β-LACTAMASE INHIBITORS......Page 286
Products......Page 287
Semisynthetic Derivatives......Page 290
Oral Cephalosporins......Page 291
β-Lactamase Resistance......Page 294
Antipseudomonal Cephalosporins......Page 296
Classification......Page 297
Products......Page 298
Future Developments in Cephalosporin Design......Page 304
MONOBACTAMS......Page 305
Chemistry......Page 306
Microbial Resistance......Page 307
Structure–Activity Relationships......Page 308
Products......Page 309
Structure of the Tetracyclines......Page 313
Spectrum of Activity......Page 315
Structure–Activity Relationships......Page 316
Products......Page 317
MACROLIDES......Page 320
Products......Page 321
LINCOMYCINS......Page 325
Products......Page 326
POLYPEPTIDES......Page 327
Polymyxin B Sulfate......Page 330
UNCLASSIFIED ANTIBIOTICS......Page 332
NEWER ANTIBIOTICS......Page 336
REVIEW QUESTIONS......Page 338
REFERENCES......Page 339
SELECTED READING......Page 341
CLASSIFICATION OF VIRUSES......Page 342
Immunization......Page 343
THE INFECTIOUS PROCESS FOR A VIRUS......Page 345
Chemoprophylaxis Influenza......Page 348
Inhibitors of DNA Polymerase......Page 351
Reverse Transcriptase Inhibitors......Page 355
NEWER AGENTS FOR THE TREATMENT OF HIV INFECTION......Page 358
Nonnucleoside Reverse Transcriptase Inhibitors......Page 359
HIV Protease Inhibitors......Page 360
Chemokine Receptor Binders......Page 363
Combination Antiviral Therapy......Page 364
REFERENCES......Page 365
INTRODUCTION......Page 367
Alkylating Agents......Page 370
Individual Agents......Page 380
Pyrimidine Drugs......Page 384
Purine Drugs......Page 390
Products......Page 391
ANTIBIOTICS AND NATURAL PRODUCTS......Page 395
Actinomycins......Page 396
Anthracyclines......Page 397
Individual Agents......Page 400
Epipodophyllotoxins......Page 401
Camptothecins......Page 403
Bleomycin......Page 406
Vinca Alkaloids......Page 408
Taxanes......Page 410
PROTEIN KINASE INHIBITORS......Page 412
MISCELLANEOUS COMPOUNDS......Page 418
REVIEW QUESTIONS......Page 422
REFERENCES......Page 423
SELECTED READING......Page 424
Radioactivity and Nuclear Medicine......Page 425
Radionuclide Production......Page 427
Biological Effects of Radiation......Page 428
Radiopharmaceuticals......Page 429
Fluorine Radiochemistry......Page 430
Indium Radiochemistry......Page 431
Iodine Radiochemistry......Page 433
Technetium Radiochemistry......Page 434
Thallium Radiochemistry......Page 441
Radiography and Computed Tomography......Page 442
Magnetic Resonance Imaging......Page 448
REVIEW QUESTIONS......Page 452
SELECTED READING......Page 453
WEB SITES OF INTEREST......Page 454
ANXIOLYTIC, SEDATIVE, AND HYPNOTIC AGENTS......Page 455
GABAA Receptors, Benzodiazepines, and Related Compounds......Page 456
Melatonin Receptor Agonist: Ramelteon......Page 463
Barbiturates......Page 464
Structure–Activity Relationships......Page 465
Miscellaneous Sedative–Hypnotics......Page 466
Alcohols and Their Carbamate Derivatives......Page 467
ANTIPSYCHOTICS......Page 469
Phenothiazines......Page 470
Ring Analogs of Phenothiazines: Benzazepines, Dibenzoxazepines, and Dibenzodiazepines......Page 475
Fluorobutyrophenones......Page 477
Antimanic Agents......Page 480
REVIEW QUESTIONS......Page 481
SELECTED READING......Page 482
Dopamine Receptors......Page 483
Dopaminergic Pathways......Page 484
PARKINSON DISEASE......Page 485
MAO-B Inhibitors......Page 486
Dopamine Agonists......Page 487
COMT Inhibitors......Page 489
Typical Antipsychotic Agents......Page 490
Phenothiazines and Thioxanthenes......Page 491
Atypical Antipsychotic Agents......Page 495
REVIEW QUESTIONS......Page 500
REFERENCES......Page 501
Classification of Epileptic Seizures and Recommended Initial Drug Therapy......Page 503
Voltage-Gated Ion Channels as Targets for Anticonvulsants......Page 504
GABAA Receptors as Targets for Anticonvulsants......Page 505
Valproic Acid (Depakote, Depakene, Depacon)......Page 506
Phenytoin (Dilantin, Kapseals, Phenytek) and Fosphenytoin (Cerebyx)......Page 507
Carbamazepine (Tegretol) and Oxcarbazepine (Trileptal)......Page 509
Gabapentin (Neurontin) and Pregabalin (Lyrica)......Page 510
Novel Broad-Spectrum Anticonvulsants......Page 511
Anticonvulsants Acts on a Selective Molecular Target......Page 512
REVIEW QUESTIONS......Page 513
REFERENCES......Page 514
SELECTED READING......Page 515
ANALEPTICS......Page 516
METHYLXANTHINES......Page 517
CENTRAL SYMPATHOMIMETIC AGENTS (PSYCHOMOTOR STIMULANTS)......Page 518
Monoamine Oxidase Inhibitors......Page 521
Monoamine Reuptake Inhibitors......Page 522
Tricyclic Antidepressants......Page 523
Selective Serotonin Reuptake Inhibitors......Page 525
Selective Serotoninergic Reuptake Inhibitors and 5-HT2A Antagonists......Page 526
MISCELLANEOUS CNS-ACTING DRUGS......Page 527
1β-Arylamino Hallucinogens......Page 528
Depressant–Intoxicant......Page 529
SELECTED READING......Page 530
Biosynthesis......Page 531
Storage, Release, Uptake, and Metabolism......Page 534
Adrenergic Receptor Subtypes......Page 536
α-Adrenergic Receptors......Page 537
β-Adrenergic Receptors......Page 538
Drugs Affecting Catecholamine Biosynthesis......Page 540
Drugs Affecting Catecholamine Storage and Release......Page 542
Direct-Acting Sympathomimetics......Page 543
Indirect-Acting Sympathomimetics......Page 555
Sympathomimetics with a Mixed Mechanism of Action......Page 556
α-Blockers......Page 557
β-Blockers......Page 561
ACKNOWLEDGMENT......Page 566
REVIEW QUESTIONS......Page 567
REFERENCES......Page 568
SELECTED READING......Page 569
CHAPTER OVERVIEW......Page 570
Nicotinic Receptors......Page 571
Muscarinic Receptors......Page 572
CHOLINERGIC NEUROCHEMISTRY......Page 575
Cholinergic Stereochemistry......Page 576
Structure–Activity Relationships......Page 578
CHOLINERGIC RECEPTOR ANTAGONISTS......Page 579
Products......Page 580
Cholinesterase Inhibitors......Page 582
Reversible Inhibitors......Page 584
Irreversible Inhibitors......Page 589
Products......Page 590
Structure–Activity Relationships......Page 593
Therapeutic Actions......Page 595
Structural Considerations......Page 596
Products......Page 597
Products......Page 600
Aminoalcohol Ethers......Page 603
Aminoalcohols......Page 604
Aminoamides......Page 606
Miscellaneous......Page 607
GANGLIONIC BLOCKING AGENTS......Page 608
Depolarizing Ganglionic Blocking Agents......Page 609
Nondepolarizing Noncompetitive Ganglionic Blocking Agents......Page 610
NEUROMUSCULAR BLOCKING AGENTS......Page 611
Curare and Curare Alkaloids......Page 612
Synthetic Compounds with Curariform Activity......Page 613
REFERENCES......Page 617
The Renin–Angiotensin System and Hypertension......Page 619
Angiotensin-Converting Enzyme Inhibitors......Page 621
ACE-INHIBITOR PRODRUGS......Page 622
ANGIOTENSIN ANTAGONISTS......Page 624
ANGIOTENSIN II BLOCKERS......Page 625
RENIN INHIBITORS......Page 626
REVIEW QUESTIONS......Page 627
REFERENCES......Page 628
ANTIANGINAL AGENTS AND VASODILATORS......Page 629
Nitrovasodilators......Page 630
Calcium Antagonists......Page 634
Antithrombotic Agents......Page 639
Cardiac Electrophysiology......Page 641
Mechanisms of Arrhythmias......Page 642
Classes of Antiarrhythmic Drugs......Page 643
pH and Activity......Page 644
ANTIHYPERTENSIVE AGENTS......Page 649
Lipoprotein Classes......Page 659
Hyperlipoproteinemias......Page 660
HMG-CoA Reductase Inhibitors......Page 664
Mechanism of Blood Coagulation......Page 666
Anticoagulant Mechanisms......Page 667
Platelet Aggregation and Inhibitors......Page 668
SYNTHETIC HYPOGLYCEMIC AGENTS......Page 670
Sulfonylureas......Page 671
Nonsulfonylureas—Metaglinides......Page 673
α-Glucosidase Inhibitors......Page 674
ANTITHYROID DRUGS......Page 675
REVIEW QUESTIONS......Page 676
REFERENCES......Page 677
DISORDERS OF GLUCOSE METABOLISM: DIABETES AND THE METABOLIC SYNDROME......Page 678
Insulins and Modified Insulins......Page 679
Sulfonylureas and Glinides......Page 680
Thiazolidinediones (Glitazones)......Page 693
Biguanides......Page 697
α-Glucosidase Inhibitors......Page 699
Amylin Analogs......Page 701
Incretin System Modulating Agents: Incretin Mimetics and Dipeptidyl Peptidase Type 4 Inhibitors......Page 702
Glucose Elevating Agents......Page 706
GONADOTROPINS, GONADOTROPIN-RELEASING HORMONE, AND GNRH RECEPTOR AGONISTS AND ANTAGONISTS......Page 707
Gonadotropin-Releasing Hormone Agonists......Page 709
Gonadotropin-Releasing Hormone Antagonists......Page 711
REVIEW QUESTIONS......Page 713
REFERENCES......Page 715
Osteoporosis......Page 717
Bisphosphonates......Page 718
Calcitonin-Salmon (sCT; Miacalcin, Calcimar)......Page 720
Hyperparathyroidism......Page 721
REFERENCES......Page 722
The Ideal Inhaled Anesthetic......Page 723
Structure–Activity Relationships of the Volatile General Anesthetics......Page 724
Mechanism of Action of the Inhaled Anesthetics......Page 725
General Anesthetic Monographs, Individual Products Including Adverse Reactions......Page 726
Propofol......Page 728
Ketamine......Page 729
Physiology of Nerve Fibers and Neurotransmission......Page 730
Neuronal Membrane Ion Permeability During an Action Potential......Page 731
Ligand-Gated Sodium Channel Structure and Function......Page 732
Mechanism of Action of Local Anesthetics......Page 734
SARs of Local Anesthetics......Page 735
Vasoconstrictors Used in Combination with Local Anesthetics......Page 736
The Ester Local Anesthetics......Page 737
The Amino Amide Local Anesthetics......Page 738
Future Directions of Local Anesthetic Research......Page 741
REVIEW QUESTIONS......Page 742
REFERENCES......Page 743
Biosynthesis and Distribution......Page 745
Storage and Release......Page 746
Histamine Receptors and Histamine-Mediated Physiologic Functions......Page 747
Mechanism of Action......Page 749
General Pharmacological and Therapeutic Considerations......Page 751
First-Generation Antihistamine Classes......Page 753
Second-Generation Antihistamines......Page 765
INHIBITION OF HISTAMINE RELEASE: MAST CELL STABILIZERS......Page 769
RECENT ANTIHISTAMINE DEVELOPMENTS: THE “DUAL-ACTING” ANTIHISTAMINES......Page 771
Structural Derivation of the “H2-Antagonists”......Page 772
Other Antiulcer and Gastric Acid Hypersecretory Disease Therapies: Proton Pump Inhibitors......Page 777
HISTAMINE H3- AND H4-RECEPTOR LIGANDS......Page 785
REFERENCES......Page 786
Acute and Chronic Pain......Page 788
Opioid Receptor Discovery and Endogenous Ligands......Page 789
Opioid Receptors......Page 790
4,5-Epoxymorphinans......Page 794
Morphinans......Page 797
4-Phenylpiperidines and 4-Anilidopiperidines......Page 798
Diphenylheptanes......Page 800
Miscellaneous......Page 801
Mixed Agonist/Antagonist......Page 802
Opioid Antagonists......Page 803
Mechanism of Action and NSAID-Induced Side Effects......Page 804
Structure–Activity Relationships of NSAIDs......Page 805
Aspirin and Salicylic Acid Derivatives......Page 808
The Conventional Nonselective Cyclooxygenase Inhibitors......Page 810
The Analgesic Antipyretics: Acetaminophen (Paracetamol) and Related Analogs......Page 815
DISEASE-MODIFYING ANTIRHEUMATIC DRUGS......Page 818
Synthetic Disease-Modifying Antirheumatic Drugs......Page 819
Risk Factors......Page 821
Treatment of Acute Gouty Arthritis......Page 822
Pathophysiology of Migraine......Page 823
Structure–Activity Relationship......Page 824
Mechanism of Action......Page 825
Antimigraine Drugs Acting on 5-HT1B/1D Receptors......Page 826
REFERENCES......Page 827
STEROID BIOSYNTHESIS......Page 831
CHANGES TO MODIFY PHARMACOKINETIC PROPERTIES OF STEROIDS......Page 834
STEROID HORMONE RECEPTORS......Page 835
Structure of Steroid Hormone Receptors......Page 836
Structure of Steroid Hormone–Receptor Complexes......Page 837
Pituitary Gonadotropins: Luteinizing Hormone and Follicle-Stimulating Hormone......Page 838
Estrogens......Page 839
Progestins......Page 849
Ovulation Inhibitors and Related Hormonal Contraceptives......Page 853
Combined Estrogen/Progestin Hormone Replacement Therapy......Page 858
Structural Classes: Anabolic Androgenic Steroids......Page 859
Therapeutic Uses of Anabolic Androgenic Steroids......Page 860
Androgens and Sports......Page 861
Anabolic Androgenic Steroid Products......Page 862
Antiandrogen Products......Page 863
Inhibition of 5α-Reductase......Page 864
Endogenous Corticosteroids......Page 865
Biosynthesis......Page 866
Biological Activities of Mineralocorticoids and Glucocorticoids......Page 867
Structural Classes: Mineralocorticoids and Glucocorticoids......Page 868
Therapeutic Uses of Adrenal Cortex Hormones......Page 871
Mineralocorticoid and Glucocorticoid Products......Page 872
ACKNOWLEDGMENT......Page 876
REVIEW QUESTIONS......Page 877
REFERENCES......Page 878
HISTORY OF EICOSANOID DISCOVERY......Page 880
EICOSANOID BIOSYNTHESIS......Page 881
DESIGN OF EICOSANOID DRUGS......Page 884
COMMERCIALLY AVAILABLE ESSENTIAL FATTY ACID SUPPLEMENTS......Page 887
EICOSANOIDS APPROVED FOR HUMAN CLINICAL USE......Page 888
VETERINARY USES OF PROSTANOIDS......Page 890
SELECTED READING......Page 891
PROTEIN HYDROLYSATES......Page 892
Conformational Features of Protein Structure......Page 893
Factors Affecting Protein Structure......Page 894
Color Tests and Miscellaneous Separation and Identification Methods......Page 895
Products......Page 896
Relation of Structure and Function......Page 897
Classification......Page 899
Products......Page 900
Hormones from the Hypothalamus......Page 902
Pituitary Hormones......Page 903
Somatostatin......Page 906
Neurohypophyseal Hormones (Oxytocin, Vasopressin)......Page 907
Pancreatic Hormones......Page 909
Gastrointestinal Hormones......Page 915
Parathyroid Hormone......Page 916
Plasmakinins......Page 917
Hemoglobin......Page 918
rDNA Technology......Page 919
BIOTECHNOLOGY-DERIVED PHARMACEUTICAL PRODUCTS......Page 921
REFERENCES......Page 925
SELECTED READING......Page 926
INTRODUCTION......Page 927
Vitamin A......Page 929
Vitamin D......Page 935
Vitamin E......Page 939
Vitamin K......Page 944
Vitamin B1......Page 947
Vitamin B2......Page 950
Vitamin B3......Page 951
Vitamin B5......Page 954
Vitamin B6......Page 956
Vitamin B7......Page 959
Vitamin B9......Page 960
Vitamin B12......Page 963
Vitamin C......Page 966
REVIEW QUESTIONS......Page 968
REFERENCES......Page 969
SELECTED READING......Page 972
HISTORICAL ASPECTS......Page 973
AN HERB IS A DRUG......Page 974
Echinacea......Page 975
Feverfew......Page 976
Saint John’s Wort......Page 977
Garlic......Page 979
Ephedra......Page 980
Ginkgo Biloba......Page 981
Ginseng......Page 982
Milk Thistle......Page 983
Herbal Drugs Used in the Treatment of Cancer......Page 984
Licorice......Page 985
REFERENCES......Page 986
APPENDIX: Calculated Log P, Log D, and pKa......Page 988
INDEX......Page 996