Preface xi
Contributing Authors xiii
Section I. Drugs Treating Infectious Diseases 1
Chapter 1. Nirmatrelvir (Paxlovid with Ritonavir): A 3-Chymotrypsin-like Protease Inhibitor for Treating SARS-CoV-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 17
4.1 Pharmacokinetics of Nirmatrelvir 17
4.2 Metabolism of Nirmatrelvir 17
5 Efficacy and Safety 18
6 Synthesis 19
6.1 Scale-up Route 19
6.2 Manufacturing Route 23
7 Summary 24
References 25
Chapter 2. Doravirine (Pifeltro): A Third-generation Nonnucleoside Reverse Transcriptase Inhibitor as a Treatment of HIV-1 Infection 29
Jie Jack li
1 Background 30
2 Pharmacology 32
3 Structure–Activity Relationship (SAR) 38
4 Pharmacokinetics and Drug Metabolism 43
5 Efficacy and Safety 45
6 Synthesis 46
7 Summary 49
References 49
Chapter 3. Cabotegravir (Vocabria): An HIV Integrase Strand Transfer Inhibitor for Treating HIV Infection 53
Jie Jack li
1 Background 54
2 Pharmacology 54
2.1 HIV Integrase 54
2.2 First-Generation HIV Integrase Inhibitors 58
2.3 Second-Generation HIV Integrase Inhibitors 61
2.4 Integrase–LEDGF/p75 Allosteric Inhibitors 63
3 Structure–Activity Relationship (SAR) 65
4 Pharmacokinetics and Drug Metabolism 68
5 Efficacy and Safety 69
6 Synthesis 70
7 Summary 74
References 74
Chapter 4. Lenacapavir (Sunlenca): A Long-acting HIV-1 Capsid Protein Inhibitor for Treating HIV Infection 77
Jie Jack li
1 Background 78
2 Pharmacology 79
3 Structure–Activity Relationship (SAR) 85
4 Pharmacokinetics and Drug Metabolism 89
5 Efficacy and Safety 90
6 Synthesis 90
7 Summary 95
References 95
Chapter 5. Fostemsavir (Rukobia): An HIV-1 gp120-Direceted Attachment Inhibitor for Treating AIDS 97
Tao Wang and Xiang li
1 Background 97
2 Pharmacology 99
3 Structure–Activity Relationship (SAR) 100
4 Pharmacokinetics and Drug Metabolism 106
5 Efficacy and Safety 109
6 Synthesis 110
7 Summary 116
References 117
Chapter 6. Oteseconazole (Vivjoa): A CYP51 Inhibitor for Treating Recurrent Vulvovaginal Candidiasis 121
Charles L. Lail III and Timothy J. Hagen
1 Background 121
2 Pharmacology 130
3 Structure–Activity Relationship (SAR) 132
4 Pharmacokinetics and Drug Metabolism 135
5 Efficacy and Safety 136
6 Synthesis 137
7 Summary 141
References 141
Section II. Oncology Drugs 147
Chapter 7. Futibatinib (Lytgobi): A Selective Irreversible FGFR1?4 Inhibitor 149
Faridoon and Guiping Zhang
1 Background 149
2 Pharmacology 152
3 Structure–Activity Relationship (SAR) 154
4 Pharmacokinetics and Drug Metabolism 158
5 Efficacy and Safety 158
6 Synthesis 159
7 Summary 163
References 163
Chapter 8. Pacritinib (Vonjo): A Dual JAK2/IRAK1 Inhibitor for Treating Myelofibrosis 167
Faridoon and Guiping Zhang
1 Background 167
2 Pharmacology 169
3 Structure–Activity Relationship (SAR) 172
4 Pharmacokinetics and Drug Metabolism 176
5 Efficacy and Safety 178
6 Synthesis 179
7 Summary 183
References 183
Chapter 9. Tucatinib (Tukysa): An Oral, Selective HER2 Inhibitor for the Treatment of HER2-positive Solid Tumors 187
Fengtao Zhou and Ke Ding
1 Background 188
2 Pharmacology 189
3 Pharmacokinetics and Drug Metabolism 190
4 Efficacy and Safety 191
5 Synthesis 192
6 Summary 196
References 197
Chapter 10. Tazemetostat (Tazverik): An EZH2 Inhibitor for Treatment of Epithelioid Sarcoma and Follicular Lymphoma 199
Ruheng Zhao and Timothy A. Cernak
1 Background 199
2 Pharmacology 200
3 Structure–Activity Relationship (SAR) 202
4 Pharmacokinetics and Drug Metabolism 207
5 Efficacy and Safety 208
6 Synthesis 209
7 Summary 212
References 212
Section III. CNS Drugs 215
Chapter 11. Ozanimod (Zeposia): An S1P Receptor Modulator for Treating Multiple Sclerosis and Inflammatory Bowel Diseases 217
Shaohui Yu and Xi Wang
1 Background 217
2 Pharmacology 220
3 Drug Metabolism and Pharmacokinetics 226
4 Structure–Activity Relationship (SAR) 228
5 Efficacy and Safety 232
6 Synthesis 236
7 Summary 239
References 240
Chapter 12. Ciprofol (Cipepofol): A γ-Aminobutyric Acid Receptor Agonist for Induction of Anesthesia 251
Ji Zhang and Dao-Qian Chen
1 Background 252
2 Pharmacology 255
3 Structure–Activity Relationship (SAR) 256
4 Pharmacokinetics and Drug Metabolism 261
5 Efficacy and Safety 263
6 Synthesis 264
7 Summary 268
References 268
Chapter 13. Rimegepant (Nurtec ODT): A CGRP Receptor Antagonist as a Treatment of Episodic Migraine 275
Yuqi Lavender Zha and Guanglin Luo
1 Background 276
2 Pharmacology 278
3 Structure–Activity Relationship (SAR) 281
4 Pharmacokinetics and Drug Metabolism 287
5 Efficacy and Safety 287
6 Synthesis 289
7 Summary 293
References 293
Chapter 14. Daridorexant (Quviviq): An Antagonist of Orexin Receptors for Treating Insomnia 299
Dexi Yang
1 Background 299
2 Pharmacology 304
3 Structure–Activity Relationship (SAR) 305
4 Pharmacokinetics and Drug Metabolism 311
5 Efficacy and Safety 312
6 Synthesis 314
7 Summary 318
References 318
Section IV. Anti-inflammatory Drugs 323
Chapter 15. Deucravacitinib (Sotyktu): A First-in-Class Deuterated TYK2 Inhibitor for the Treatment of Plaque Psoriasis 325
Daljit Matharu
1 Background 325
2 Pharmacology 330
3 Structure–Activity Relationship (SAR) 331
4 Pharmacokinetics and Drug Metabolism 341
5 Efficacy and Safety 342
6 Synthesis 34 4
7 Summary 356
References 357
Section V. Miscellaneous Drugs 361
Chapter 16. Bremelanotide (Vyleesi): A Melanocortin Receptor Agonist for Treating Female Hypoactive Sexual Desire Disorder 363
Yan Wang
1 Background 363
2 Pharmacology 366
3 Structure–Activity Relationship (SAR) 369
4 Pharmacokinetics and Drug Metabolism 370
5 Efficacy and Safety 371
6 Synthesis 372
7 Summary 377
References 377
Chapter 17. Odevixibat (Bylvay): A Selective Inhibitor of the Ileal Bile Acid Transporter 381
Andrew Outlaw and Timothy A. Cernak
1 Background 382
2 Pharmacology 384
3 Early Inhibitors of the Ileal Bile Acid Transporter 388
4 Structure–Activity Relationship (SAR) 388
5 Pharmacokinetics and Drug Metabolism 393
6 Efficacy and Safety 393
7 Synthesis 394
8 Summary 397
References 398
Index 403
