Preface xi
Contributing Authors xiii
Part I Infectious Disease Drugs 1
Chapter 1 Relebactam (Recarbrio), A ß-Lactamase Inhibitor for the Treatment of cIAI/cUTI/HABP/ VABP 3
1 Background 3
2 Pharmacology 5
3 Structure-Activity Relationship (SAR) 6
4 Pharmacokinetics and Drug Metabolism 9
5 Efficacy and Safety 10
6 Syntheses 10
7 Summary 14
8 References 14
Chapter 2 Vaborbactam (in Combination with Meropenem as Vabomere), a Non-ß-Lactam ß-Lactamase Inhibitor for Treatment of Complicated Urinary Tract Infections and Pyelonephritis 17
1 Background 17
2 Discovery Medicinal Chemistry 21
3 Vaborbactam/Vabomere Clinical Trials 27
4 Vaborbactam Medicinal Chemistry Synthesis 29
5 Vaborbactam Process Chemistry Synthesis 30
6 Conclusions 37
7 References 38
Chapter 3 Baloxavir Marboxil (Xofluza), A Cap-Dependent Endonuclease Inhibitor for Treating Influenza 41
1 Background 41
2 Mechanism of Action 43
3 Structure-Activity Relationship 45
4 Pharmacokinetics and Drug Metabolism 49
5 Efficacy and Safety 50
6 Syntheses 50
7 Summary 54
8 References 54
Chapter 4 Process Chemistry Development of the HIV Protease Inhibitor Drug Kaletra: A Mixture of Ritonavir and Lopinavir 57
1 Background 58
2 Ritonavir Portion of Kaletra Synthesis 58
3 Discovery Synthesis of the Ritonavir Core 60
4 Discovery Synthesis of Ritonavir Wing Pieces 63
5 Large-Scale Process Chemistry Synthesis of the Ritonavir Core 65
6 Large-Scale Syntheses of the 5-Hydroxymethyl Thiazole Wing Portion 69
7 The Large-Scale Coupling of the Thiazole Wing Pieces to the Core 70
8 Lopinavir Portion of Kaletra- Discovery Synthesis and Process Development 72
9 Discovery Synthesis of Lopinavir 73
10 Discovery Synthesis of Wing Pieces 74
11 Process Improvements to the Wing Pieces 76
12 Optimization of Lopinavir Synthesis with Intermediates 78
13 Conclusions 81
14 References 81
Chapter 5 Eravacycline (Xerava), A Novel and Completely Synthetic Fluorocycline Antibiotic 85
1 Background 85
2 Pharmacology 89
3 Structure-Activity Relationship (SAR) 91
4 Pharmacokinetics and Drug Metabolism 93
5 Efficacy and Safety 93
6 Syntheses 93
7 Summary 98
8 References 99
Chapter 6 Albuvirtide (Aikening), A gp41 Analog as an HIV-1 Fusion Inhibitor 101
1 Background 101
2 Pharmacology 102
3 Structure-Activity Relationship (SAR) 106
4 Pharmacokinetics and Drug Metabolism 107
5 Efficacy and Safety 110
6 Syntheses 112
7 Summary 114
8 References 115
Part II Cancer Drugs 119
Chapter 7 Darolutamide (Nubeqa): An Androgen Receptor Antagonist for Treating Nonmetastatic, Castration-Resistant 121
1 Background 121
2 Pharmacology 124
3 Structure-Activity Relationship (SAR) 126
4 Pharmacokinetics and Drug Metabolism 132
5 Efficacy and Safety 134
6 Syntheses 135
7 The Future 137
8 References 138
Chapter 8 Venetoclax (Venclexta): A BCL-2 Antagonist for Treating Chronic Lymphocytic Leukemia 143
1 Background 143
2 Pharmacology 144
3 Structure-Activity Relationship (SAR) 147
4 Pharmacokinetics and Drug Metabolism 153
5 Efficacy and Safety 154
6 Syntheses 155
7 Summary 160
8 References 161
Chapter 9 Osimertinib (Tagrisso), A Potent and Selective Third-Generation EGFR Inhibitor for the Treatment of Both Sensitizing and T790M-Resistance Mutations 165
1 Background 165
2 Pharmacology 167
3 Structure-Activity Relationship (SAR) 170
4 Pharmacokinetics and Drug Metabolism 173
5 Efficacy and Safety 174
6 Syntheses 175
7 Summary 180
8 References 180
Chapter 10 Sotorasib (LUMAKRA), An Irreversible Covalent Inhibitor of KRASG12C 183
1 Background 183
2 Pharmacology 184
3 Structure-Activity Relationship (SAR) 186
4 Pharmacokinetics and Drug Metabolism 191
5 Efficacy and Safety 191
6 Syntheses 192
7 Summary 196
8 References 196
Chapter 11 Lorlatinib (Lorbrena), An ALK Inhibitor for Treating NSCLC 201
1 Background 201
2 Pharmacology 203
3 Structure-Activity Relationship (SAR) 205
4 Pharmacokinetics and Drug Metabolism 210
5 Efficacy and Safety 211
6 Syntheses 213
7 Summary 226
8 References 227
Chapter 12 Niraparib (Zejula) A Small Molecule, PARP1/2 Inhibitor for Treating Breast, Ovarian, and Pancreatic Cancers 231
2 Pharmacology 235
3 Structure-Activity Relationship (SAR) 238
4 Pharmacokinetics and Drug Metabolism 243
5 Efficacy and Safety 243
6 Syntheses 244
7 Summary 248
8 References 248
Chapter 13 Selinexor (Xpovio), An XPO1 Inhibitor and a New Class of Therapeutics for Treating Multiple Myeloma 253
1 Exportin1 (XPO1) 253
2 Overview of Multiple Myeloma 255
3 Development of Selinexor 256
4 Pharmacology and Mechanism 257
5 Pharmacokinetics, Pharmacodynamics and Drug Metabolism 258
6 Efficacy and Safety 259
7 Syntheses 259
8 Summary and Future 262
9 References 262
Part III Cns Drugs 265
Chapter 14 Sage 217 (Zuranolone) for Treating Major of Depressive Disorder267
1 Background 267
2 Pharmacology 270
3 Structure-Activity Relationship (SAR) 272
4 Pharmacokinetics and Drug Metabolism 279
5 Efficacy and Safety 280
6 Syntheses 281
7 Summary 282
8 References 283
Chapter 15 Risdiplam (Evrysdi), A Small Molecule, SMN2-directed RNA Splicing Modifier for Treating Spinal Muscular Atrophy 287
1 Background 287
2 Pharmacology 289
3 Structure-Activity Relationship (SAR) 290
4 Pharmacokinetics and Drug Metabolism 297
5 Efficacy and Safety 297
6 Syntheses 298
7 Summary 300
8 References 301
Part IV Miscellaneous Drugs 305
Chapter 16 Esaxerenone (Minnebro), An Oral, Non-steroidal, Selective Mineralocorticoid Receptor Blocker for the Treatment of Essential Hypertension307
1 Background 307
2 Pharmacology 310
3 Structure-Activity Relationship (SAR) 311
4 Pharmacokinetics and Drug Metabolism 313
5 Efficacy and Safety 315
6 Syntheses 316
7 Summary 320
8 References 321
Chapter 17 Voclosporin (Lupkynis), A Macrocyclic Peptide Inhibitor of Calcineurin for the Treatment of Lupus Nephritis 323
1 Background 323
2 Pharmacology 326
3 Structure-Activity Relationship (SAR) 326
4 Pharmacokinetics and Drug Metabolism 329
5 Efficacy and Safety 331
6 Syntheses 333
7 References 336
Chapter 18 Computational-Aided Drug Design 339
1 Background 339
2 Structure-based Drug Design (SBDD) 341
3 Ligand-based Drug Design (LBDD) 352
4 Summary 361
5 References 362
Index 373
