Table of Contents
Preface xiContributors 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
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