Chemistry and Pharmacology of Drug Discovery

Jie Jack Li, PhD is the CSO of GenHouse Bio. Previously, he was VP of Discovery Chemistry at ChemPartner, 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.

• Preface xiContributing Authors xiiiSection I. Drugs Treating Infectious Diseases 1Chapter 1. Nirmatrelvir (Paxlovid with Ritonavir): A 3-Chymotrypsin-like Protease Inhibitor for Treating SARS-CoV-2 Infection 3Jie Jack li1 Background 42 Pharmacology 52.1 The Coronavirus 52.2 The 3CL Protease 62.3 The Mechanism of Action of Nirmatrelvir 93 Structure–Activity Relationship (SAR) 103.1 The Pyrrolidone Substituent at P1 103.2 Dimethylcyclopropylproline at P2 113.3 The Nitrile Warhead at P1’ 133.4 Lead Optimization 144 Pharmacokinetics and Drug Metabolism 174.1 Pharmacokinetics of Nirmatrelvir 174.2 Metabolism of Nirmatrelvir 175 Efficacy and Safety 186 Synthesis 196.1 Scale-up Route 196.2 Manufacturing Route 237 Summary 24References 25Chapter 2. Doravirine (Pifeltro): A Third-generation Nonnucleoside Reverse Transcriptase Inhibitor as a Treatment of HIV-1 Infection 29Jie Jack li1 Background 302 Pharmacology 323 Structure–Activity Relationship (SAR) 384 Pharmacokinetics and Drug Metabolism 435 Efficacy and Safety 456 Synthesis 467 Summary 49References 49Chapter 3. Cabotegravir (Vocabria): An HIV Integrase Strand Transfer Inhibitor for Treating HIV Infection 53Jie Jack li1 Background 542 Pharmacology 542.1 HIV Integrase 542.2 First-Generation HIV Integrase Inhibitors 582.3 Second-Generation HIV Integrase Inhibitors 612.4 Integrase–LEDGF/p75 Allosteric Inhibitors 633 Structure–Activity Relationship (SAR) 654 Pharmacokinetics and Drug Metabolism 685 Efficacy and Safety 696 Synthesis 707 Summary 74References 74Chapter 4. Lenacapavir (Sunlenca): A Long-acting HIV-1 Capsid Protein Inhibitor for Treating HIV Infection 77Jie Jack li1 Background 782 Pharmacology 793 Structure–Activity Relationship (SAR) 854 Pharmacokinetics and Drug Metabolism 895 Efficacy and Safety 906 Synthesis 907 Summary 95References 95Chapter 5. Fostemsavir (Rukobia): An HIV-1 gp120-Direceted Attachment Inhibitor for Treating AIDS 97Tao Wang and Xiang li1 Background 972 Pharmacology 993 Structure–Activity Relationship (SAR) 1004 Pharmacokinetics and Drug Metabolism 1065 Efficacy and Safety 1096 Synthesis 1107 Summary 116References 117Chapter 6. Oteseconazole (Vivjoa): A CYP51 Inhibitor for Treating Recurrent Vulvovaginal Candidiasis 121Charles L. Lail III and Timothy J. Hagen1 Background 1212 Pharmacology 1303 Structure–Activity Relationship (SAR) 1324 Pharmacokinetics and Drug Metabolism 1355 Efficacy and Safety 1366 Synthesis 1377 Summary 141References 141Section II. Oncology Drugs 147Chapter 7. Futibatinib (Lytgobi): A Selective Irreversible FGFR1‒4 Inhibitor 149Faridoon and Guiping Zhang1 Background 1492 Pharmacology 1523 Structure–Activity Relationship (SAR) 1544 Pharmacokinetics and Drug Metabolism 1585 Efficacy and Safety 1586 Synthesis 1597 Summary 163References 163Chapter 8. Pacritinib (Vonjo): A Dual JAK2/IRAK1 Inhibitor for Treating Myelofibrosis 167Faridoon and Guiping Zhang1 Background 1672 Pharmacology 1693 Structure–Activity Relationship (SAR) 1724 Pharmacokinetics and Drug Metabolism 1765 Efficacy and Safety 1786 Synthesis 1797 Summary 183References 183Chapter 9. Tucatinib (Tukysa): An Oral, Selective HER2 Inhibitor for the Treatment of HER2-positive Solid Tumors 187Fengtao Zhou and Ke Ding1 Background 1882 Pharmacology 1893 Pharmacokinetics and Drug Metabolism 1904 Efficacy and Safety 1915 Synthesis 1926 Summary 196References 197Chapter 10. Tazemetostat (Tazverik): An EZH2 Inhibitor for Treatment of Epithelioid Sarcoma and Follicular Lymphoma 199Ruheng Zhao and Timothy A. Cernak1 Background 1992 Pharmacology 2003 Structure–Activity Relationship (SAR) 2024 Pharmacokinetics and Drug Metabolism 2075 Efficacy and Safety 2086 Synthesis 2097 Summary 212References 212Section III. CNS Drugs 215Chapter 11. Ozanimod (Zeposia): An S1P Receptor Modulator for Treating Multiple Sclerosis and Inflammatory Bowel Diseases 217Shaohui Yu and Xi Wang1 Background 2172 Pharmacology 2203 Drug Metabolism and Pharmacokinetics 2264 Structure–Activity Relationship (SAR) 2285 Efficacy and Safety 2326 Synthesis 2367 Summary 239References 240Chapter 12. Ciprofol (Cipepofol): A γ-Aminobutyric Acid Receptor Agonist for Induction of Anesthesia 251Ji Zhang and Dao-Qian Chen1 Background 2522 Pharmacology 2553 Structure–Activity Relationship (SAR) 2564 Pharmacokinetics and Drug Metabolism 2615 Efficacy and Safety 2636 Synthesis 2647 Summary 268References 268Chapter 13. Rimegepant (Nurtec ODT): A CGRP Receptor Antagonist as a Treatment of Episodic Migraine 275Yuqi Lavender Zha and Guanglin Luo1 Background 2762 Pharmacology 2783 Structure–Activity Relationship (SAR) 2814 Pharmacokinetics and Drug Metabolism 2875 Efficacy and Safety 2876 Synthesis 2897 Summary 293References 293Chapter 14. Daridorexant (Quviviq): An Antagonist of Orexin Receptors for Treating Insomnia 299Dexi Yang1 Background 2992 Pharmacology 3043 Structure–Activity Relationship (SAR) 3054 Pharmacokinetics and Drug Metabolism 3115 Efficacy and Safety 3126 Synthesis 3147 Summary 318References 318Section IV. Anti-inflammatory Drugs 323Chapter 15. Deucravacitinib (Sotyktu): A First-in-Class Deuterated TYK2 Inhibitor for the Treatment of Plaque Psoriasis 325Daljit Matharu1 Background 3252 Pharmacology 3303 Structure–Activity Relationship (SAR) 3314 Pharmacokinetics and Drug Metabolism 3415 Efficacy and Safety 3426 Synthesis 34 47 Summary 356References 357Section V. Miscellaneous Drugs 361Chapter 16. Bremelanotide (Vyleesi): A Melanocortin Receptor Agonist for Treating Female Hypoactive Sexual Desire Disorder 363Yan Wang1 Background 3632 Pharmacology 3663 Structure–Activity Relationship (SAR) 3694 Pharmacokinetics and Drug Metabolism 3705 Efficacy and Safety 3716 Synthesis 3727 Summary 377References 377Chapter 17. Odevixibat (Bylvay): A Selective Inhibitor of the Ileal Bile Acid Transporter 381Andrew Outlaw and Timothy A. Cernak1 Background 3822 Pharmacology 3843 Early Inhibitors of the Ileal Bile Acid Transporter 3884 Structure–Activity Relationship (SAR) 3885 Pharmacokinetics and Drug Metabolism 3936 Efficacy and Safety 3937 Synthesis 3948 Summary 397References 398Index 403