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 xiiiI. Infectious Diseases 1Chapter 1. Raltegravir (Isentress), The First-in-class HIV-1 Integrase Inhibitor 3Julianne A. Hunt1.1 Background 31.2 Pharmacology 51.3 Structure-Activity Relationship (SAR) 61.4 Pharmacokinetics and Drug Metabolism 81.5 Efficacy and Safety 91.6 Syntheses 101.7 References 13Chapter 2. Maraviroc (Selzentry), The First-in-class CCR5 Antagonist for the Treatment of HIV 17David Price2.1 Background 172.2 Structure-Activity Relationship (SAR) 192.3 Pharmacokinetics and Safety 212.4 Syntheses 222.5 References 27Chapter 3. Darunavir (Prezista), A HIV-1 Protease Inhibitor for Treatment of Multidrug Resistant HIV 29Arun K. Ghosh and Cuthbert D. Martyr3.1 Background 293.2 Pharmacology 323.3 Structure-Activity Relationship (SAR) 323.4 Pharmacokinetics and Drug Metabolism 333.5 Efficacy and Safety 333.6 Syntheses 343.7 References 42II. Cancer 45Chapter 4. Decitabine (Dacogen), A DNA Methyltransferase Inhibitor for Cancer 47Jennifer A. Van Camp4.1 Background 474.2 Pharmacology 494.3 Structure-Activity Relationship (SAR) 494.4 Pharmacokinetics and Drug Metabolism 504.5 Efficacy and Safety 504.6 Syntheses 514.7 References 54Chapter 5. Capecitabine (Xeloda), An Oral Chemotherapy Agent 57R. Jason Herr5.1 Background 575.2 Pharmacology 605.3 Structure-Activity Relationship (SAR) 625.4 Pharmacokinetics and Efficacy 635.5 Syntheses 645.6 References 70Chapter 6. Sorafenib (Nexavar), A Multi-kinase Inhibitor for Advanced Renal Cell Carcinoma and Unresectable Hepatocellular Carcinoma 73Shuanghua Hu6.1 Background 736.2 Pharmacology 756.3 Structure-Activity Relationship (SAR) 776.4 Pharmacokinetics and Drug Metabolism 786.5 Efficacy and Safety 786.6 Syntheses 796.7 References 84Chapter 7. Sunitinib (Sutent), An Angiogenesis Inhibitor 87Martin Pettersson7.1 Background 877.2 Discovery and Development 897.3 Syntheses 917.3.1 Discovery Route 917.3.2 Process Route 927.4 References 97Chapter 8. Bortezomib (Velcade), A First-in-class Proteasome Inhibitor 99Benjamin S. Greener and David S. Millan8.1 Background 998.2 Pharmacology 1018.3 Structure-Activity Relationship (SAR) 1028.4 Pharmacokinetics and Drug Metabolism 1048.5 Efficacy and Safety 1048.6 Syntheses 1058.7 References 109Chapter 9. Pazopanib (Votrient), A VEGFR Tyrosine Kinase Inhibitor for Cancer 111Ji Zhang and Jie Jack Li9.1 Background 1119.2 Pharmacology 1139.3 Structure?Activity Relationship (SAR) 1149.4 Pharmacokinetics and Drug Metabolism 1179.5 Efficacy and Safety 1189.6 Syntheses 1189.7 Other VEGFR Inhibitors in Development: Vandetanib and Cediranib 1209.8 References 121III. Cardiovascular and Metabolic Diseases 123Chapter 10. Sitagliptin (Januvia), A Treatment for Type 2 Diabetes 125Scott D. Edmondson, Feng Xu, and Joseph D. Armstrong III10.1 Background 12510.2 Pharmacology 12610.3 Structure-Activity Relationship (SAR) 12710.4 Pharmacokinetics and Drug Metabolism 12810.5 Efficacy and Safety 12910.6 Syntheses 13010.7 References 138Chapter 11. Aliskiren (Tekturna), The First-in-class Renin Inhibitor for Hypertension 141Victor J. Cee11.1 Background 14111.2 Pharmacology 14411.3 Structure-Activity Relationship (SAR) n14511.4 Pharmacokinetics and Drug Metabolism 14611.5 Efficacy and Safety 14711.6 Syntheses 14811.7 References 156Chapter 12. Vernakalant (Kynapid), An Investigational Drug for the Treatment of Atrial Fibrillation 159David L. Gray12.1 Background 15912.2 Pharmacology 16312.3 Structure-Activity Relationship (SAR) 16312.4 Pharmacokinetics and Drug Metabolism 16412.5 Efficacy and Safety 16512.6 Syntheses 16612.7 References 171Chapter 13. Conivaptan (Vaprisol), Vasopressin V1a and V2 Antagonist for Hyponatremia 175Brian A. Lanman13.1 Background 17513.2 Pharmacology 17713.3 Structure-Activity Relationship (SAR) 17913.4 Pharmacokinetics and Drug Metabolism 18113.5 Efficacy and Safety 18213.6 Syntheses 18313.7 References 189Chapter 14. Rivaroxaban (Xarelto), A Factor Xa Inhibitor for the Treatment of Thrombotic Events 191Ji Zhang and Jason Crawford14.1 Background 19114.2 Pharmacology 19314.3 Structure?Activity Relationship (SAR) 19414.4 Pharmacokinetics and Drug Metabolism 19614.5 Efficacy and Safety 19714.6 Syntheses 19814.7 Compounds in Development: Apixaban and Otamixaban 20314.8 References 204Chapter 15. Endothelin Antagonists for the Treatment of Pulmonary Arterial Hypertension 207David Edmonds15.1 Background 20815.2 Treatment of PAH 20915.3 Endothelin Antagonists 21115.4 Synthesis of Bosentan 21515.5 Synthesis of Sitaxsentan 21715.6 Synthesis of Ambrisentan 21915.7 Conclusion 22115.8 References 221IV. Central Nervous System Diseases 225Chapter 16. Varenicline (Chantix), An α4β2 Nicotinic Receptor Partial Agonist for Smoking Cessation 227Jotham W. Coe, Frank R. Busch and Robert A. Singer16.1 Background 22716.2 Discovery Chemistry Program 22916.3 Pharmacology 23116.4 Pharmacokinetics and Drug Metabolism 23116.5 Efficacy and Safety 23216.6 Syntheses 23216.7 References 244Chapter 17. Donepezil, Rivastigmine, Galantamine: Cholinesterase Inhibitors for Alzheimer's Disease 249Subas Sakya and Kapil Karki17.1 Background 25017.2 Pharmacology 25117.3 Structure?Activity Relationship (SAR) 25317.4 Pharmacokinetics and Drug Metabolism 25617.5 Efficacy and Safety 25817.6 Synthesis of Donepezil 25917.7 Synthesis of Rivastigmine 26217.8 Synthesis of Galantamine 26517.9 References 271Chapter 18. Aprepitant (Emend), A NK1 Receptor Antagonist for the Treatment of Post-chemotherapy Emesis 275John A. Lowe, III18.1 Background 27518.2 In Vitro Pharmacology and Structure-Activity Relationships 27918.3 In Vivo Pharmacology 28118.4 Pharmacokinetics and Drug Metabolism 28218.5 Efficacy and Safety 28218.6 Syntheses 28318.7 References 289Chapter 19. Armodafinil (Nuvigil), A Psychostimulant for the Treatment of Narcolepsy 291Ji Zhang and Jason Crawford19.1 Background 29119.2 Pharmacology 29319.3 Pharmacokinetics and Drug Metabolism 29419.4 Efficacy and Safety 29519.5 Synthesis 29619.6 References 303V. Miscellaneous 307Chapter 20. Raloxifene (Evista), A Selective Estrogen Receptor Modulator (SERM) 309Marta Piñeiro-Núñez20.1 Background 30920.2 Mechanism of Action 31320.3 Pharmacokinetics and Drug Metabolism 31320.4 Efficacy and Safety 31420.5 Syntheses 31520.6 References 325Chapter 21. Latanoprost (Xalatan), A Prostanoid FP Agonist for Glaucoma 329Sajiv K. Nair and Kevin E. Henegar21.1 Background 32921.2 Syntheses 33121.3 References 337Index 339

"All chapters are very well written, and the used schemes and tables are conveniently arranged. The information and explanations given are strengthened by well-chosen examples and so the reader can easily follow the discussion. The comprehensive referenced literature placed at the end of each chapter enables further reading, and a detailed keyword index in combination with a logically structured Table of Content allows fast access to the topic of interest." (ChemMedChem, 2010)