Innovative Drug Synthesis

ISBN-13: 9781118820056 / Angielski / Twarda / 2015 / 360 str.

Jie Jack Li; Douglas S. Johnson

Opis

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

Spis treści

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

O autorze

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).

Blurb

Discover the cutting–edge science driving the medicinal chemistry and synthesis of the latest drugs

Continuing the tradition of the acclaimed prior volumes on drug synthesis, Innovative Drug Synthesis illustrates how chemistry, biology, pharmacokinetics, and related disciplines come together to produce successful medicines. This book covers all aspects of the medicinal chemistry of the latest drugs and the cutting–edge science associated with them. With authoritative coverage by distinguished editors and authors analyzing the pros and cons of different synthetic routes, the book demystifies the process of modern drug discovery for practitioners and researchers.

Other highlights include:

• Summary of respective disease area, important properties and SAR (structure activity relationship), and chemical synthesis routes/options for each covered drug
• A step–by–step breakdown of today′s drug discovery process for professionals and students
• Chapters on drugs that have achieved breakthrough therapy designation such as sofosbuvir, palbociclib, and more

Innovative Drug Synthesis shows that whether drug synthesis is in early development or the process stage, the ability to design elegant and economical synthetic routes is often a major factor making a drug a commercial winner. Easy to follow and stacked with valuable information on the present and future direction of medicinal chemistry, Innovative Drug Synthesis paints a clear and complete picture of this complex subject.