Modern Drug Synthesis

JIE JACK LI is a chemist at Bristol-Myers Squibb Company in Wallingford, Connecticut. He is the coauthor of various books, including Palladium in Heterocyclic Chemistry, Name Reactions: A Collection of Detailed Reaction Mechanisms and Synthetic Applications, Name Reactions in Heterocyclic Chemistry, Contemporary Drug Synthesis, The Art of Drug Synthesis, Name Reactions for Functional Group Transformations, Name Reactions for Homologations, Parts 1 and 2, and Name Reactions for Carbocyclic Ring Formations. DOUGLAS JOHNSON is a medicinal chemist and project leader at Pfizer in Groton, Connecticut. He is a coauthor on more than forty publications and patents, including the books The Art of Drug Synthesis and Contemporary Drug Synthesis.

Preface xi Contributors xiii

I. Infectious Diseases 1

Chapter 1. Raltegravir (Isentress), The First-in-class HIV-1 Integrase Inhibitor 3
Julianne A. Hunt

1.1 Background 3

1.2 Pharmacology 5

1.3 Structure-Activity Relationship (SAR) 6

1.4 Pharmacokinetics and Drug Metabolism 8

1.5 Efficacy and Safety 9

1.6 Syntheses 10

1.7 References 13

Chapter 2. Maraviroc (Selzentry), The First-in-class CCR5 Antagonist for the Treatment of HIV 17
David Price

2.1 Background 17

2.2 Structure-Activity Relationship (SAR) 19

2.3 Pharmacokinetics and Safety 21

2.4 Syntheses 22

2.5 References 27

Chapter 3. Darunavir (Prezista), A HIV-1 Protease Inhibitor for Treatment of Multidrug Resistant HIV 29
Arun K. Ghosh and Cuthbert D. Martyr

3.1 Background 29

3.2 Pharmacology 32

3.3 Structure-Activity Relationship (SAR) 32

3.4 Pharmacokinetics and Drug Metabolism 33

3.5 Efficacy and Safety 33

3.6 Syntheses 34

3.7 References 42

II. Cancer 45

Chapter 4. Decitabine (Dacogen), A DNA Methyltransferase Inhibitor for Cancer 47
Jennifer A. Van Camp

4.1 Background 47

4.2 Pharmacology 49

4.3 Structure-Activity Relationship (SAR) 49

4.4 Pharmacokinetics and Drug Metabolism 50

4.5 Efficacy and Safety 50

4.6 Syntheses 51

4.7 References 54

Chapter 5. Capecitabine (Xeloda), An Oral Chemotherapy Agent 57
R. Jason Herr

5.1 Background 57

5.2 Pharmacology 60

5.3 Structure-Activity Relationship (SAR) 62

5.4 Pharmacokinetics and Efficacy 63

5.5 Syntheses 64

5.6 References 70

Chapter 6. Sorafenib (Nexavar), A Multi-kinase Inhibitor for Advanced Renal Cell Carcinoma and Unresectable Hepatocellular Carcinoma 73
Shuanghua Hu

6.1 Background 73

6.2 Pharmacology 75

6.3 Structure-Activity Relationship (SAR) 77

6.4 Pharmacokinetics and Drug Metabolism 78

6.5 Efficacy and Safety 78

6.6 Syntheses 79

6.7 References 84

Chapter 7. Sunitinib (Sutent), An Angiogenesis Inhibitor 87
Martin Pettersson

7.1 Background 87

7.2 Discovery and Development 89

7.3 Syntheses 91

7.3.1 Discovery Route 91

7.3.2 Process Route 92

7.4 References 97

Chapter 8. Bortezomib (Velcade), A First-in-class Proteasome Inhibitor 99
Benjamin S. Greener and David S. Millan

8.1 Background 99

8.2 Pharmacology 101

8.3 Structure-Activity Relationship (SAR) 102

8.4 Pharmacokinetics and Drug Metabolism 104

8.5 Efficacy and Safety 104

8.6 Syntheses 105

8.7 References 109

Chapter 9. Pazopanib (Votrient), A VEGFR Tyrosine Kinase Inhibitor for Cancer 111
Ji Zhang and Jie Jack Li

9.1 Background 111

9.2 Pharmacology 113

9.3 Structure?Activity Relationship (SAR) 114

9.4 Pharmacokinetics and Drug Metabolism 117

9.5 Efficacy and Safety 118

9.6 Syntheses 118

9.7 Other VEGFR Inhibitors in Development: Vandetanib and Cediranib 120

9.8 References 121

III. Cardiovascular and Metabolic Diseases 123

Chapter 10. Sitagliptin (Januvia), A Treatment for Type 2 Diabetes 125
Scott D. Edmondson, Feng Xu, and Joseph D. Armstrong III

10.1 Background 125

10.2 Pharmacology 126

10.3 Structure-Activity Relationship (SAR) 127

10.4 Pharmacokinetics and Drug Metabolism 128

10.5 Efficacy and Safety 129

10.6 Syntheses 130

10.7 References 138

Chapter 11. Aliskiren (Tekturna), The First-in-class Renin Inhibitor for Hypertension 141
Victor J. Cee

11.1 Background 141

11.2 Pharmacology 144

11.3 Structure-Activity Relationship (SAR) n145

11.4 Pharmacokinetics and Drug Metabolism 146

11.5 Efficacy and Safety 147

11.6 Syntheses 148

11.7 References 156

Chapter 12. Vernakalant (Kynapid), An Investigational Drug for the Treatment of Atrial Fibrillation 159
David L. Gray

12.1 Background 159

12.2 Pharmacology 163

12.3 Structure-Activity Relationship (SAR) 163

12.4 Pharmacokinetics and Drug Metabolism 164

12.5 Efficacy and Safety 165

12.6 Syntheses 166

12.7 References 171

Chapter 13. Conivaptan (Vaprisol), Vasopressin V1a and V2 Antagonist for Hyponatremia 175
Brian A. Lanman

13.1 Background 175

13.2 Pharmacology 177

13.3 Structure-Activity Relationship (SAR) 179

13.4 Pharmacokinetics and Drug Metabolism 181

13.5 Efficacy and Safety 182

13.6 Syntheses 183

13.7 References 189

Chapter 14. Rivaroxaban (Xarelto), A Factor Xa Inhibitor for the Treatment of Thrombotic Events 191
Ji Zhang and Jason Crawford

14.1 Background 191

14.2 Pharmacology 193

14.3 Structure?Activity Relationship (SAR) 194

14.4 Pharmacokinetics and Drug Metabolism 196

14.5 Efficacy and Safety 197

14.6 Syntheses 198

14.7 Compounds in Development: Apixaban and Otamixaban 203

14.8 References 204

Chapter 15. Endothelin Antagonists for the Treatment of Pulmonary Arterial Hypertension 207
David Edmonds

15.1 Background 208

15.2 Treatment of PAH 209

15.3 Endothelin Antagonists 211

15.4 Synthesis of Bosentan 215

15.5 Synthesis of Sitaxsentan 217

15.6 Synthesis of Ambrisentan 219

15.7 Conclusion 221

15.8 References 221

IV. Central Nervous System Diseases 225

Chapter 16. Varenicline (Chantix), An α4β2 Nicotinic Receptor Partial Agonist for Smoking Cessation 227
Jotham W. Coe, Frank R. Busch and Robert A. Singer

16.1 Background 227

16.2 Discovery Chemistry Program 229

16.3 Pharmacology 231

16.4 Pharmacokinetics and Drug Metabolism 231

16.5 Efficacy and Safety 232

16.6 Syntheses 232

16.7 References 244

Chapter 17. Donepezil, Rivastigmine, Galantamine: Cholinesterase Inhibitors for Alzheimer's Disease 249
Subas Sakya and Kapil Karki

17.1 Background 250

17.2 Pharmacology 251

17.3 Structure?Activity Relationship (SAR) 253

17.4 Pharmacokinetics and Drug Metabolism 256

17.5 Efficacy and Safety 258

17.6 Synthesis of Donepezil 259

17.7 Synthesis of Rivastigmine 262

17.8 Synthesis of Galantamine 265

17.9 References 271

Chapter 18. Aprepitant (Emend), A NK1 Receptor Antagonist for the Treatment of Post-chemotherapy Emesis 275
John A. Lowe, III

18.1 Background 275

18.2 In Vitro Pharmacology and Structure-Activity Relationships 279

18.3 In Vivo Pharmacology 281

18.4 Pharmacokinetics and Drug Metabolism 282

18.5 Efficacy and Safety 282

18.6 Syntheses 283

18.7 References 289

Chapter 19. Armodafinil (Nuvigil), A Psychostimulant for the Treatment of Narcolepsy 291
Ji Zhang and Jason Crawford

19.1 Background 291

19.2 Pharmacology 293

19.3 Pharmacokinetics and Drug Metabolism 294

19.4 Efficacy and Safety 295

19.5 Synthesis 296

19.6 References 303

V. Miscellaneous 307

Chapter 20. Raloxifene (Evista), A Selective Estrogen Receptor Modulator (SERM) 309
Marta Piñeiro-Núñez

20.1 Background 309

20.2 Mechanism of Action 313

20.3 Pharmacokinetics and Drug Metabolism 313

20.4 Efficacy and Safety 314

20.5 Syntheses 315

20.6 References 325

Chapter 21. Latanoprost (Xalatan), A Prostanoid FP Agonist for Glaucoma 329
Sajiv K. Nair and Kevin E. Henegar

21.1 Background 329

21.2 Syntheses 331

21.3 References 337

Index 339