Case studies of 20 successful FDA-approved drugs, from biological rationale to clinical efficacy studies and state-of-the-art applications
Chemistry and Pharmacology of Drug Discovery illustrates how chemistry, biology, pharmacokinetics, and a host of disciplines come together to produce successful medicines, discussing a total of 20 drugs that are all FDA-approved post 2021—some of which are first-in-class and revolutionary.
The four sections in this book cover Infectious Disease, Cancer Drugs, CNS Drugs, and Miscellaneous Drugs. Each chapter covers background material on the drug class and/or disease indication and key aspects relevant to the discovery of the drug, including structure-activity relationships, pharmacokinetics, drug metabolism, efficacy, and safety.
This book is contributed to by various veterans and well-known experts in medical chemistry, many of whom discovered the drugs they reviewed, leading to tremendous quality and depth of insight.
Some of the drugs covered in Chemistry and Pharmacology of Drug Discovery include:
- Nirmatrelvir (Paxlovid with Ritonavir), a 3-chymotrypsin-like protease inhibitor for treating SARS-Co V-2 infection
- Doravirine (Pifeltro), a third-generation non-nucleoside reverse transcriptase inhibitor for the treatment of HIV-1 infection
- Oteseconazole (Vivjoa), a CYP51 inhibitor for treating recurrent vulvovaginal candidiasis, and Rimegepant (Nurtec ODT), a CGRP antagonist for treating migraine
- Ciprofol (Cipepofol), a γ-Aminobutyric acid receptor agonist for induction of anesthesia, and Ozanimod (Zeposia), an S1P receptor antagonist for treating multiple sclerosis
- Deucravacitinib (Sotyktu), a first-in-class deuterated TYK2 inhibitor for the treatment of plaque psoriasis
Chemistry and Pharmacology of Drug Discovery serves as an excellent and highly authoritative learning resource for medicinal, organic, synthetic, and process chemists as well as research scientists in lead optimization and process development.
Tabla de materias
Preface xi
Contributors xiii
PART I. DRUGS TREATING INFECTIOUS DISEASES 1
Chapter 1. Nirmatrelvir (Paxlovid with Ritonavir): A 3-Chymotrypsin-like Protease Inhibitor for Treating SARS-Co V-2 Infection 3
Jie Jack Li
1 Background 4
2 Pharmacology 5
2.1 The Coronavirus 5
2.2 The 3CL Protease 6
2.3 The Mechanism of Action of Nirmatrelvir 9
3 Structure–Activity Relationship (SAR) 10
3.1 The Pyrrolidone Substituent at P1 10
3.2 Dimethylcyclopropylproline at P2 11
3.3 The Nitrile Warhead at P1′ 13
3.4 Lead Optimization 14
4 Pharmacokinetics and Drug Metabolism 16
4.1 Pharmacokinetics of Nirmatrelvir 16
4.2 Metabolism of Nirmatrelvir 16
5 Efficacy and Safety 17
6 Syntheses 18
7 Summary 23
8 References 23
Chapter 2. Doravirine (Pifeltro): A Third-generation Non-nucleoside Reverse Transcriptase Inhibitor as a Treatment of HIV-1 Infection 27
Jie Jack Li
1 Background 27
2 Pharmacology 30
3 Structure–Activity Relationship (SAR) 36
4 Pharmacokinetics and Drug Metabolism 40
5 Efficacy and Safety 42
6 Syntheses 43
7 Summary 46
8 References 46
Chapter 3. Cabotegravir (Vocabria), HIV Integrase Strand Transfer Inhibitor for Treating HIV Infection 51
Jie Jack Li
1 Background 52
2 Pharmacology 52
2.1 HIV Integrase 52
2.2 First-Generation HIV Integrase Inhibitors 55
2.3 Second-Generation HIV Integrase Inhibitors 59
2.4 Integrase–LEDGF/p75 Allosteric Inhibitors 61
3 Structure–Activity Relationship (SAR) 63
4 Pharmacokinetics and Drug Metabolism 65
5 Efficacy and Safety 66
6 Syntheses 67
7 Summary 71
8 References 72
Chapter 4. Lenacapavir (Sunlenca): A Long-acting HIV-1 Capsid Protein Inhibitor for Treating HIV Infection 75
Jie Jack Li
1 Background 76
2 Pharmacology 77
3 Structure–Activity Relationship (SAR) 83
4 Pharmacokinetics and Drug Metabolism 87
5 Efficacy and Safety 88
6 Synthesis 88
7 Summary 93
8 References 93
Chapter 5. Fostemsavir (Rukobia), HIV-1 Attachment Inhibitor 95
Tao Wang and Xiang Li
1 Background 95
2 Pharmacology 97
3 Structure–Activity Relationship (SAR) 98
4 Pharmacokinetics and Drug Metabolism 104
5 Efficacy and Safety 107
6 Syntheses 108
7 Summary 114
8 References 115
Chapter 6. Oteseconazole (Vivjoa), A CYP51 Inhibitor for
Treating Recurrent Vulvovaginal Candidiasis 119
Charles Lail and Timothy Hagen
1 Background 119
2 Pharmacology 128
3 Structure–Activity Relationship (SAR) 130
4 Pharmacokinetics and Drug Metabolism 133
5 Efficacy and Safety 134
6 Syntheses 135
7 Summary 139
8 References 139
PART II. CANCER DRUGS 145
Chapter 7. Futibatinib (Lytgobi), A Selective Irreversible FGFR1‒4 Inhibitor 147
Faridoon and Zhang Guiping
1 Background 147
2 Pharmacology 150
3 Structure–Activity Relationship (SAR) 156
4 Pharmacokinetics and Drug Metabolism 156
5 Efficacy and Safety 156
6 Syntheses 157
7 Summary 161
8 References 161
Chapter 8. Pacritinib (Vonjo), A Dual JAK2/IRAK1 Inhibitor for Treating Myelofibrosis 163
Faridoon and Zhang Guiping
1 Background 163
2 Pharmacology 165
3 Structure–Activity Relationship (SAR) 168
4 Pharmacokinetics and Drug Metabolism 172
5 Efficacy and Safety 173
6 Syntheses 175
7 Summary 179
8 References 179
Chapter 9. Tucatinib (Tukysa), An Oral, Selective HER2 Inhibitor for the Treatment of HER2-positive Solid Tumors 183
Fengtao Zhou and Ke Ding
1 Background 184
2 Pharmacology 185
3 Pharmacokinetics and Drug Metabolism 186
4 Efficacy and Safety 187
5 Syntheses 188
6 Summary 192
7 References 193
Chapter 10. Tazemetostat (Tazverik), An EZH2 Inhibitor for Treatment of Epithelioid Sarcoma and Follicular Lymphoma 195
Ruheng Zhao and Timothy A. Cernak
1 Background 195
2 Pharmacology 196
3 Structure–Activity Relationship (SAR) 198
4 Pharmacokinetics and Drug Metabolism 203
5 Efficacy and Safety 204
6 Syntheses 205
7 Summary 208
8 References 208
PART III. CNS DRUGS 211
Chapter 11. Ozanimod (Zeposia), An S1P receptor Antagonist for Treating Multiple Sclerosis 213
Shaohui Yu and Xi Wang
1 Background 213
2 Pharmacology 216
3 Pharmacokinetics and Drug Metabolism 222
4 Structure–Activity Relationship (SAR) 224
5 Efficacy and Safety 229
6 Syntheses 232
7 Summary 235
8 References 236
Chapter 12. Ciprofol (Cipepofol): A γ-Aminobutyric Acid Receptor Agonist for Induction of Anesthesia 245
Ji Zhang and Dao-Qian Chen
1 Background 246
2 Pharmacology 249
3 Structure–Activity Relationship (SAR) 250
4 Pharmacokinetics and Drug Metabolism 255
5 Efficacy and Safety 257
6 Syntheses 258
7 Summary 262
8 References 262
Chapter 13. Rimegepant (Nurtec ODT), a CGRP Antagonist for Treating Migraine 267
Guanglin Luo and Yuqi Lavender Zha
1 Background 268
2 Pharmacology 270
3 Structure–Activity Relationship (SAR) 273
4 Pharmacokinetics and Drug Metabolism 278
5 Efficacy and Safety 279
6 Syntheses 281
7 Summary 284
8 References 285
Chapter 14. Daridorexant (Quviviq), An Antagonist of Orexin Receptors for Treating Insomnia 291
Dexi Yang
1 Background 291
2 Pharmacology 296
3 Structure–Activity Relationship (SAR) 297
4 Pharmacokinetics and Drug Metabolism 303
5 Efficacy and Safety 304
6 Syntheses 306
7 Summary 310
8 References 310
PART IV. ANTI-INFLAMMATORY DRUGS 315
Chapter 15. Deucravacitinib (Sotyktu): A First-in-class Deuterated TYK2 Inhibitor for the Treatment of Plaque Psoriasis 317
Daljit Matharu
1 Background 317
2 Pharmacology 322
3 Structure–Activity Relationship (SAR) 323
4 Pharmacokinetics and Drug Metabolism 333
5 Efficacy and Safety 334
6 Syntheses 336
7 Summary 348
8 References 349
PART V. MISCELLANEOUS DRUGS 353
Chapter 16. Bremelanotide (Vyleesi), A Melanocortin Receptor Agonist for Treating Female Hypoactive Sexual Desire Disorder 355
Yan Wang
1 Background 355
2 Pharmacology 358
3 Structure–Activity Relationship (SAR) 360
4 Pharmacokinetics and Drug Metabolism 362
5 Efficacy and Safety 362
6 Syntheses 363
7 Summary 368
8 References 368
Chapter 17. Odevixibat (Bylvay), A Selective Inhibitor of the Ileal Bile Acid Transporter 373
Andrew Outlaw and Timothy A. Cernak
1 Background 374
2 Pharmacology 376
3 Structure–Activity Relationship (SAR) 380
4 Pharmacokinetics and Drug Metabolism 384
5 Efficacy and Safety 384
6 Syntheses 385
7 Summary 388
8 References 389
Index 393
Sobre el autor
Jie Jack Li, Ph D is the CSO of Gen House Bio. Previously, he was VP of Discovery Chemistry at Chem Partner, an Associate Professor of Chemistry at the University of San Francisco, and a Medicinal Chemist at Pfizer and Bristol-Myers Squibb. He has authored or edited over 30 books, many published by Wiley.
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