Содержание
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
