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

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-CoV-2 infectionDoravirine (Pifeltro), a third-generation non-nucleoside reverse transcriptase inhibitor for the treatment of HIV-1 infectionOteseconazole (Vivjoa), a CYP51 inhibitor for treating recurrent vulvovaginal candidiasis, and Rimegepant (Nurtec ODT), a CGRP antagonist for treating migraineCiprofol (Cipepofol), a γ-Aminobutyric acid receptor agonist for induction of anesthesia, and Ozanimod (Zeposia), an S1P receptor antagonist for treating multiple sclerosisDeucravacitinib (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.