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Innovative Drug Synthesis

Innovative Drug Synthesis

Jie Jack Li (Editor), Douglas S. Johnson (Editor)

ISBN: 978-1-118-81995-1

Dec 2015

360 pages

Description

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 / options
  • Includes case studies in each chapter
  • Illustrates how chemistry, biology, pharmacokinetics, and a host of disciplines come together to produce successful medicines
  • Explains 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 Structure–Activity 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 Structure–Activity 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 Structure–Activity 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 Structure–Activity 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 Structure–Activity 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 Structure–Activity 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 Structure–Activity 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 Structure–Activity 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 Structure–Activity 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 Structure–Activity 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 Structure–Activity 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 Structure–Activity 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 Structure–Activity 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