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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5371_Библиотеки_им_академика_М_И_Перельмана
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Chemistry and Pharmacology of
Drug Discovery
Chemistry and Pharmacology of
Drug Discovery
Edited by
Jie Jack Li
Copyright © 2025 by John Wiley & Sons, Inc. A l l rights reserved, including rights for
text a nd data mining and training o f artificial technologies o r similar technologies.
Published by John Wiley & Sons, Inc., Hoboken, New Jersey.
Published simultaneously in Canada.
No part of this publication may be reproduced, stored in a retrieval system, or transmitted
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Library of Congress Cataloging-in-Publication Data applied for
Hardback ISBN: 9781394225125
Cover Design: Wiley
Cover Image: Courtesy of Faridoon
____________________________________
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Contents
Preface
Contributing Authors
SECTION I. DRUGS TREATING INFECTIOUS DISEASES 1
Chapter 1. Nirmatrelvir (Paxlovid with Ritonavir): A 3Chymotrypsin-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 P
3.2 Dimethylcyclopropylproline at P
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
10
1
11
2
xi
xiii
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
5 Efficacy and Safety 45
6 Synthesis 46
7
Pharmacokinetics and Drug Metabolism 43
Summary 49
References 49
Chapter 3. Cabotegravir (Vocabria) An HIV Integrase Strand
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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
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
Synthesis
:
70
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
3 Structure–Activity Relationship (SAR)
4 Pharmacokinetics and Drug Metabolism 106
5 Efficacy and Safety 109
6 Synthesis 110
7 Summary
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
:
99
100
116
:
3 Structure–Activity Relationship (SAR) 132
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4 Pharmacokinetics and Drug Metabolism 135
5 Efficacy and Safety 136
6 Synthesis 137
7 Summary
References 141
141
SECTION II. 147
Chapter 7. Futibatinib (Lytgobi) A Selective Irreversible
FGFR1‒4 Inhibitor 149
Faridoon and Zhang
1 Background 149
2 Pharmacology
3 Structure–Activity Relationship (SAR) 154
4 Pharmacokinetics and Drug Metabolism 158
5 Efficacy and Safety
6 Synthesis
7 Summary
References
Chapter 8. Pacritinib (Vonjo) A Dual JAK2/IRAK1 Inhibitor for
Treating Myelofibrosis
Faridoon and Zhang Guiping
1 Background 167
2 Pharmacology
3 Structure–Activity Relationship (SAR)
4 Pharmacokinetics and Drug Metabolism
5 Efficacy and Safety
6 Synthesis
7 Summary
References
ONCOLOGY DRUGS
:
Guiping
152
158
159
163
163
:
167
169
172
176
178
179
183
183
Chapter 9. Tucatinib (Tukysa) An Oral, Selective HER2 Inhibitor
for the Treatment of HER2-positive Solid Tumors
Fengtao Zhou and Ke Ding
1 Background 188
2 Pharmacology 189
3 Pharmacokinetics and Drug Metabolism 190
4
5 Synthesis 192
6
:
187
Efficacy and Safety 191
Summary 196
References 197
Chapter 10. Tazemetostat (Tazverik) An EZH2 Inhibitor for
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Treatment of Epithelioid Sarcoma and Follicular Lymphoma 199
Ruheng Zhao and Timothy A. Cernak
1 Background 199
2
3
4 Pharmacokinetics and Drug Metabolism 207
5
6 Synthesis 209
7
SECTION III. CNS DRUGS 215
Pharmacology 200
Structure–Activity Relationship (SAR) 202
Efficacy and Safety 208
Summary 212
References
:
212
Chapter 11. Ozanimod (Zeposia) An S1P
Treating Multiple Sclerosis and Inammatory Bowel Diseases
Shaohui Yu and Xi Wang
1 Background 217
2 Pharmacology 220
3 226
4 Structure–Activity Relationship (SAR) 228
5 Efficacy and Safety
6 Synthesis
7 Summary 239
References
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
3
4
5
6 Synthesis 264
7 Summary 268
Drug Metabolism and Pharmacokinetics
Pharmacology 255
Structure–Activity Relationship (SAR) 256
Pharmacokinetics and Drug Metabolism 261
Efficacy and Safety 263
References 268
:
Receptor Modulator for
217
232
236
240
Chapter 13. Rimegepant (Nurtec ODT)
Antagonist as a Treatment of Episodic Migraine
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
: A CGRP Receptor
275
6 Synthesis 289
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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.
Chapter 15. Deucravacitinib (Sotyktu): A First-in- lass 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
7 Summary 356
References 357
ANTI-INFLAMMATORY DRUGS 323
:
C
4
SECTION V.
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
MISCELLANEOUS DRUGS 361
:
References 377
Chapter 17. Odevixibat (Bylvay) A Selective Inhibitor of the Ileal
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Bile Acid Transporter 381
Andrew Outlaw and Timothy A. Cernak
1 Background 382
2
3 Early Inhibitors of the Ileal Bile Acid Transporter 388
4
5 Pharmacokinetics and Drug Metabolism 393
6
7
8 Summary 397
Index 403
Pharmacology 384
Structure–Activity Relationship (SAR) 388
Efficacy and Safety 393
Synthesis 394
References
:
398
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