Innovative Drug Synthesis

Jie Jack Li is an Associate Professor of chemistry at the University of San Francisco. Previously, he was a Discovery Chemist at Bristol-Myers Squibb and Pfizer. He has authored or edited over 20 books and several of those were published by Wiley, including Drug Discovery: Practices, Processes, and Perspectives, Heterocyclic Chemistry in Drug Discovery, Name Reactions in Heterocyclic Chemistry, Name Reactions for Functional Group Transformations, Contemporary Drug Synthesis, The Art of Drug Synthesis, and Modern Drug Synthesis Douglas S. Johnson is a Research Fellow and Head of Chemical Biology in the Neuroscience Medicinal Chemistry group at Pfizer Worldwide Research and Development. He is a co-author on more than 75 publications and patents and is a co-author of the book Contemporary Drug Synthesis and is an editor of The Art of Drug Synthesis, and Modern Drug Synthesis (all published by Wiley).

• Preface xiContributors xiiiPART I. INFECTIOUS DISEASES 1Chapter 1. Entecavir (Baraclude): A Carbocyclic Nucleoside for the Treatment of Chronic Hepatitis B 31 Background 32 Pharmacology 53 Structure–Activity Relationship (SAR) 64 Pharmacokinetics and Drug Metabolism 75 Efficacy and Safety 86 Syntheses 87 References 14Chapter 2. Telaprevir (Incivek) and Boceprevir (Victrelis): NS3/4A Inhibitors for Treatment for Hepatitis C Virus (HCV) 151 Background 162 Pharmacology 163 Structure–Activity Relationship (SAR) 174 PK and Drug Metabolism 205 Efficacy and Safety 226 Synthesis 247 Conclusions 388 References 39Chapter 3. Daclatasvir (Daklinza): The First-in-Class HCV NS5A Replication Complex Inhibitor 431 Background 432 Discovery Medicinal Chemistry 453 Mode of Action 484 Pharmacokinetics and Drug Metabolism 495 Efficacy and Safety 496 Syntheses 527 References 57Chapter 4. Sofosbuvir (Sovaldi): The First-in-Class HCV NS5B Nucleotide Polymerase Inhibitor 611 Background 612 Pharmacology 633 Structure–Activity Relationship (SAR) 644 Pharmacokinetics and Drug Metabolism 685 Efficacy and Safety 696 Syntheses 727 Summary 768 References 76Chapter 5. Bedaquiline (Sirturo): A Diarylquinoline that Blocks Tuberculosis ATP Synthase for the Treatment of Multi-Drug Resistant Tuberculosis 811 Background 812 Pharmacology 843 Structure–Activity Relationship (SAR) 854 Pharmacokinetics and Drug Metabolism 865 Efficacy and Safety 876 Syntheses 887 References 96PART II. CANCER 99Chapter 6. Enzalutamide (Xtandi): An Androgen Receptor Antagonist for Late-Stage Prostate Cancer 1011 Background 1012 Pharmacology 1033 Structure–Activity Relationship (SAR) 1044 Pharmacokinetics and Drug Metabolism 1085 Efficacy and Safety 1096 Synthesis 1117 Compounds in Development 1148 References 115Chapter 7. Crizotinib (Xalkori): The First-in-Class ALK/ROS Inhibitor for Non-small Cell Lung Cancer 1191 Background: Non-small Cell Lung Cancer (NSCLC) Treatment 1192 Discovery Medicinal Chemistry Effort: SAR and Lead Optimization of Compound 2 as a c-Met Inhibitor 1203 ALK and ROS in Non-small Cell Lung Cancer (NSCLC) Treatment 1274 Preclinical Model Tumor Growth Inhibition Efficacy and Pharmacology 1275 Human Clinical Trials 1286 Introduction to the Synthesis and Limitations of the Discovery Route to Crizotinib Analogs 1297 Process Chemistry: Initial Improvements 1318 Process Chemistry: Enabling Route to Crizotinib 1359 Development of the Commercial Process 14110 Commercial Synthesis of Crizotinib 14711 References 152Chapter 8. Ibrutinib (Imbruvica): The First-in-Class Btk Inhibitor for Mantle Cell Lymphoma, Chronic Lymphocytic Leukemia, and Waldenstrom's Macroglobulinemia 1571 Background 1572 Pharmacology 1593 Structure–Activity Relationship (SAR) 1594 Pharmacokinetics and Drug Metabolism 1615 Efficacy and Safety 1616 Syntheses 1627 References 164Chapter 9. Palbociclib (Ibrance): The First-in-Class CDK4/6 Inhibitor for Breast Cancer 1671 Background 1672 Pharmacology 1683 Discovery Program 1694 Preclinical Profile of Palbociclib 1755 Clinical Profile of Palbociclib 1766 Early Process Development for Palbociclib 1777 Commercial Process for Preparation of Palbociclib 1928 References 193PART III. CARDIOVASCULAR DISEASES 197Chapter 10. Ticagrelor (Brilinta) and Dabigatran Etexilate (Pradaxa): P2Y12 Platelet Inhibitors as Anti-coagulants 1991 Introduction 2002 Dabigatran Etexilate 2003 Ticagrelor 2074 The Future 2195 References 220PART IV. CNS DRUGS 223Chapter 11. Suvorexant (BELSOMRA): The First-in-Class Orexin Antagonist for Insomnia 2251 Background 2252 Pharmacology 2293 Pharmacokinetics and Drug Metabolism 2304 Efficacy and Safety 2315 Structure–Activity Relationship (SAR) 2316 Synthesis 2337 References 239Chapter 12. Lorcaserin (Belviq): Serotonin 2C Receptor Agonist for the Treatment of Obesity 2431 Background 2432 Pharmacology 2453 Structure–Activity Relationship (SAR) 2464 Pharmacokinetics and Drug Metabolism 2485 Efficacy and Safety 2496 Synthesis 2507 References 253Chapter 13. Fingolimod (Gilenya): The First Oral Treatment for Multiple Sclerosis 2551 Background 2552 Structure–Activity Relationship (SAR) 2573 Pharmacology 2594 Human Pharmacokinetics and Drug Metabolism 2605 Efficacy and Safety 2616 Syntheses 2637 Summary 2688 References 269Chapter 14. Perampanel (Fycompa): AMPA Receptor Antagonist for the Treatment of Seizure 2711 Background 2712 Pharmacology 2733 Structure–Activity Relationship (SAR) 2744 Pharmacokinetics and Drug Metabolism 2765 Efficacy and Safety 2776 Syntheses 2787 References 280PART V. ANTI-INFLAMMATORY DRUGS 283Chapter 15. Tofacitinib (Xeljanz): The First-in-Class JAK Inhibitor for the Treatment of Rheumatoid Arthritis 2851 Background 2852 Structure–Activity Relationships (SAR) 2873 Safety, Pharmacology and Pharmacokinetics 2894 Syntheses 2905 Development of the Commercial Manufacturing Process 2926 References 300PART VI. MISCELLANEOUS DRUGS 303Chapter 16. Ivacaftor (Kalydeco): A CFTR Potentiator for the Treatment of Cystic Fibrosis 3051 Background 3052 Pharmacology 3063 Structure–Activity Relationship (SAR) 3074 Pharmacokinetics and Drug Metabolism 3085 Efficacy and Safety 3106 Syntheses 3117 References 315Chapter 17. Febuxostat (Uloric): A Xanthine Oxidase Inhibitor for the Treatment of Gout 3171 Background 3172 Pharmacology 3193 Structure–Activity Relationship (SAR) 3204 Pharmacokinetics and Drug Metabolism 3215 Efficacy and Safety 3226 Syntheses 3237 Drug in Development: Lesinurad Sodium 3288 References 330Index 331