This book covers all aspects of the medicinal chemistry of the latest drugs, and the cutting-edge science associated with them. Following the editors 3 successful drug synthesis books, this provides expert analysis of the pros and cons of different synthetic routes and demystifies the process of modern drug discovery for practitioners and researchers.
Summarizes for each drug: respective disease area, important properties and SAR (structure-activity relationship), and chemical synthesis routes / optionsIncludes case studies in each chapterIllustrates how chemistry, biology, pharmacokinetics, and a host of disciplines come together to produce successful medicinesExplains the advantages of process synthesis versus the synthetic route for drug discovery
Preface xi
Contributors xiii
PART I. INFECTIOUS DISEASES 1
Chapter 1. Entecavir (Baraclude): A Carbocyclic Nucleoside for the Treatment of Chronic Hepatitis B 3
1 Background 3
2 Pharmacology 5
3 StructureActivity Relationship (SAR) 6
4 Pharmacokinetics and Drug Metabolism 7
5 Efficacy and Safety 8
6 Syntheses 8
7 References 14
Chapter 2. Telaprevir (Incivek) and Boceprevir (Victrelis): NS3/4A Inhibitors for Treatment for Hepatitis C Virus (HCV) 15
1 Background 16
2 Pharmacology 16
3 StructureActivity Relationship (SAR) 17
4 PK and Drug Metabolism 20
5 Efficacy and Safety 22
6 Synthesis 24
7 Conclusions 38
8 References 39
Chapter 3. Daclatasvir (Daklinza): The First-in-Class HCV NS5A Replication Complex Inhibitor 43
1 Background 43
2 Discovery Medicinal Chemistry 45
3 Mode of Action 48
4 Pharmacokinetics and Drug Metabolism 49
5 Efficacy and Safety 49
6 Syntheses 52
7 References 57
Chapter 4. Sofosbuvir (Sovaldi): The First-in-Class HCV NS5B Nucleotide Polymerase Inhibitor 61
1 Background 61
2 Pharmacology 63
3 StructureActivity Relationship (SAR) 64
4 Pharmacokinetics and Drug Metabolism 68
5 Efficacy and Safety 69
6 Syntheses 72
7 Summary 76
8 References 76
Chapter 5. Bedaquiline (Sirturo): A Diarylquinoline that Blocks Tuberculosis ATP Synthase for the Treatment of Multi-Drug Resistant Tuberculosis 81
1 Background 81
2 Pharmacology 84
3 StructureActivity Relationship (SAR) 85
4 Pharmacokinetics and Drug Metabolism 86
5 Efficacy and Safety 87
6 Syntheses 88
7 References 96
PART II. CANCER 99
Chapter 6. Enzalutamide (Xtandi): An Androgen Receptor Antagonist for Late-Stage Prostate Cancer 101
1 Background 101
2 Pharmacology 103
3 StructureActivity Relationship (SAR) 104
4 Pharmacokinetics and Drug Metabolism 108
5 Efficacy and Safety 109
6 Synthesis 111
7 Compounds in Development 114
8 References 115
Chapter 7. Crizotinib (Xalkori): The First-in-Class ALK/ROS Inhibitor for Non-small Cell Lung Cancer 119
1 Background: Non-small Cell Lung Cancer (NSCLC) Treatment 119
2 Discovery Medicinal Chemistry Effort: SAR and Lead Optimization of Compound 2 as a c-Met Inhibitor 120
3 ALK and ROS in Non-small Cell Lung Cancer (NSCLC) Treatment 127
4 Preclinical Model Tumor Growth Inhibition Efficacy and Pharmacology 127
5 Human Clinical Trials 128
6 Introduction to the Synthesis and Limitations of the Discovery Route to Crizotinib Analogs 129
7 Process Chemistry: Initial Improvements 131
8 Process Chemistry: Enabling Route to Crizotinib 135
9 Development of the Commercial Process 141
10 Commercial Synthesis of Crizotinib 147
11 References 152
Chapter 8. Ibrutinib (Imbruvica): The First-in-Class Btk Inhibitor for Mantle Cell Lymphoma, Chronic Lymphocytic Leukemia, and Waldenstrom's Macroglobulinemia 157
1 Background 157
2 Pharmacology 159
3 StructureActivity Relationship (SAR) 159
4 Pharmacokinetics and Drug Metabolism 161
5 Efficacy and Safety 161
6 Syntheses 162
7 References 164
Chapter 9. Palbociclib (Ibrance): The First-in-Class CDK4/6 Inhibitor for Breast Cancer 167
1 Background 167
2 Pharmacology 168
3 Discovery Program 169
4 Preclinical Profile of Palbociclib 175
5 Clinical Profile of Palbociclib 176
6 Early Process Development for Palbociclib 177
7 Commercial Process for Preparation of Palbociclib 192
8 References 193
PART III. CARDIOVASCULAR DISEASES 197
Chapter 10. Ticagrelor (Brilinta) and Dabigatran Etexilate (Pradaxa): P2Y12 Platelet Inhibitors as Anti-coagulants 199
1 Introduction 200
2 Dabigatran Etexilate 200
3 Ticagrelor 207
4 The Future 219
5 References 220
PART IV. CNS DRUGS 223
Chapter 11. Suvorexant (BELSOMRA): The First-in-Class Orexin Antagonist for Insomnia 225
1 Background 225
2 Pharmacology 229
3 Pharmacokinetics and Drug Metabolism 230
4 Efficacy and Safety 231
5 StructureActivity Relationship (SAR) 231
6 Synthesis 233
7 References 239
Chapter 12. Lorcaserin (Belviq): Serotonin 2C Receptor Agonist for the Treatment of Obesity 243
1 Background 243
2 Pharmacology 245
3 StructureActivity Relationship (SAR) 246
4 Pharmacokinetics and Drug Metabolism 248
5 Efficacy and Safety 249
6 Synthesis 250
7 References 253
Chapter 13. Fingolimod (Gilenya): The First Oral Treatment for Multiple Sclerosis 255
1 Background 255
2 StructureActivity Relationship (SAR) 257
3 Pharmacology 259
4 Human Pharmacokinetics and Drug Metabolism 260
5 Efficacy and Safety 261
6 Syntheses 263
7 Summary 268
8 References 269
Chapter 14. Perampanel (Fycompa): AMPA Receptor Antagonist for the Treatment of Seizure 271
1 Background 271
2 Pharmacology 273
3 StructureActivity Relationship (SAR) 274
4 Pharmacokinetics and Drug Metabolism 276
5 Efficacy and Safety 277
6 Syntheses 278
7 References 280
PART V. ANTI-INFLAMMATORY DRUGS 283
Chapter 15. Tofacitinib (Xeljanz): The First-in-Class JAK Inhibitor for the Treatment of Rheumatoid Arthritis 285
1 Background 285
2 StructureActivity Relationships (SAR) 287
3 Safety, Pharmacology and Pharmacokinetics 289
4 Syntheses 290
5 Development of the Commercial Manufacturing Process 292
6 References 300
PART VI. MISCELLANEOUS DRUGS 303
Chapter 16. Ivacaftor (Kalydeco): A CFTR Potentiator for the Treatment of Cystic Fibrosis 305
1 Background 305
2 Pharmacology 306
3 StructureActivity Relationship (SAR) 307
4 Pharmacokinetics and Drug Metabolism 308
5 Efficacy and Safety 310
6 Syntheses 311
7 References 315
Chapter 17. Febuxostat (Uloric): A Xanthine Oxidase Inhibitor for the Treatment of Gout 317
1 Background 317
2 Pharmacology 319
3 StructureActivity Relationship (SAR) 320
4 Pharmacokinetics and Drug Metabolism 321
5 Efficacy and Safety 322
6 Syntheses 323
7 Drug in Development: Lesinurad Sodium 328
8 References 330
Index 331
