Antiviral Drugs: From Basic Discovery Through Clinical Trials

WIESLAW M. KAZMIERSKI , PhD, has worked on novel HIV and HCV therapies in both small and large pharma settings for the last two decades, helping to advance molecules to clinical trials. Dr. Kazmierski has authored numerous peer-reviewed publications and has been named a co-inventor on many patents. He has edited scientific books and had served on journal editorial boards.

CONTRIBUTORS ix PREFACE xiii PART I HUMAN IMMUNODEFICIENCY VIRUS Section I HIV Protease Inhibitors 1 Discovery and Development of Atazanavir 3 Awny Farajallah, R. Todd Bunch, and Nicholas A. Meanwell 2 Discovery and Development of PL-100, A Novel HIV-1 Protease Inhibitor 19 Jinzi J. Wu and Joseph Musto 3 Darunavir (Prezista, TMC114): From Bench to Clinic, Improving Treatment Options for HIV-Infected Patients 31 Marie-Pierre de Bethune, Vanitha Sekar, Sabrina Spinosa-Guzman, Marc Vanstockem, Sandra De Meyer, Piet Wigerinck, and Eric Lefebvre 4 Discovery and Development of Tipranavir 47 Karen R. Romines Section II HIV Non-nucleoside Reverse Transcriptase Inhibitors 5 TMC278 (Rilpivirine): A Next-Generation NNRTI in Phase III Clinical Development for Treatment-Naive Patients 59 Jerome Guillemont, Katia Boven, Herta Crauwels, and Marie-Pierre de Bethune 6 Etravirine: From TMC125 to Intelence: A Treatment Paradigm Shift for HIV-Infected Patients 71 Koen Andries, Ann Debunne, Thomas N. Kakuda, Michael Kukla, Ruud Leemans, Johan Vingerhoets, Brian Woodfall, and Marie-Pierre de B'ethune Section III HIV Nucleoside Reverse Transcriptase Inhibitors 7 Discovery and Development of Tenofovir Disoproxil Fumarate 85 Erik De Clercq 8 Discovery and Development of Apricitabine 103 Susan Cox, John Deadman, Justine Southby, and Jonathan Coates Section IV HIV Entry Inhibitors 9 Discovery and Development of Maraviroc and PF-232798: CCR5 Antagonists for the Treatment of HIV-1 Infection 117 Patrick Dorr and Paul Stupple 10 Discovery of the CCR5 Antagonist Vicriviroc (Sch 417690/Sch-D) for the Treatment of HIV-1 Infection 137 Jayaram R. Tagat, Julie M. Strizki, and Lisa M. Dunkle 11 Discovery and Development of HIV-1 Entry Inhibitors That Target gp120 149 John F. Kadow, John Bender, Alicia Regueiro-Ren, Yasutsugu Ueda, Tao Wang, Kap-Sun Yeung, and Nicholas A. Meanwell Section V HIV Integrase Inhibitors 12 Discovery of MK-0536: A Potential Second-Generation HIV-1 Integrase Strand Transfer Inhibitor with a High Genetic Barrier to Mutation 163 Melissa S. Egbertson, John S. Wai, Mark Cameron, and R. Scott Hoerrner 13 Discovery and Development of HIV Integrase Inhibitor Raltegravir 181 Vincenzo Summa and Paola Pace 14 Elvitegravir: A Novel Monoketo Acid HIV-1 Integrase Strand Transfer Inhibitor 197 Hisashi Shinkai, Masanori Sato, and Yuji Matsuzaki PART II HEPATITIS C VIRUS Section VI Protease Inhibitors 15 Discovery and Development of Telaprevir 209 Anne-Laure Grillot, Luc J. Farmer, B. Govinda Rao, William P. Taylor, Ilan S. Weisberg, Ira M. Jacobson, Robert B. Perni, and Ann D. Kwong 16 Discovery and Development of BILN 2061 and Follow-up BI 201335 225 Montse Llinas-Brunet and Peter W. White 17 Intervention of Hepatitis C Replication Through NS3-4A, the Protease Inhibitor Boceprevir 239 Srikanth Venkatraman and F. George Njoroge 18 Discovery and Development of the HCV NS3/4A Protease Inhibitor Danoprevir (ITMN-191/RG7227) 257 Scott D. Seiwert, Karl Kossen, Lin Pan, Jyanwei Liu, and Brad O. Buckman 19 Discovery and Development of the HCV Protease Inhibitor TMC435 273 Pierre Raboisson, Gregory Fanning, Herman de Kock, Asa Rosenquist, Rene Verloes, and Kenneth Simmen Section VII HCV Polymerase Nucleoside Inhibitors 20 Discovery and Clinical Evaluation of the Nucleoside Analog Balapiravir (R1626) for the Treatment of HCV Infection 287 Klaus Klumpp and David B. Smith 21 Discovery and Development of PSI-6130/RG7128 305 Phillip A. Furman, Michael J. Otto, and Michael J. Sofia Section VIII Other HCV Inhibitors 22 Discovery of Cyclophilin Inhibitor NIM811 as a Novel Therapeutic Agent for HCV 317 Kai Lin 23 HCV Viral Entry Inhibitors 329 Flossie Wong-Staal, Guohong Liu, and Jeffrey McKelvy PART III RESPIRATORY SYNCYTIAL VIRUS INHIBITORS 24 Discovery of the RSV Inhibitor TMC353121 341 Jean-Francois Bonfanti, Gabriela Ispas, Frans Van Velsen, Wieslawa Olszewska, Tom Gevers, and Dirk Roymans 25 Discovery and Development of Orally Active RSV Fusion Inhibitors 353 Nicholas A. Meanwell, Christopher W. Cianci, and Mark R. Krystal 26 Discovery and Development of RSV604 367 Joanna Chapman and G. Stuart Cockerill PART IV INFLUENZA, HEPATITIS B, AND CYTOMEGALOVIRUS INHIBITORS 27 Discovery and Development of Influenza Virus Sialidase Inhibitor Relenza 385 Robin Thomson and Mark von Itzstein 28 Discovery and Development of Entecavir 401 Richard Wilber, Bruce Kreter, Marc Bifano, Stephanie Danetz, Lois Lehman-McKeeman, Daniel J. Tenney, Nicholas Meanwell, Robert Zahler, and Helena Brett-Smith 29 Benzimidazole Ribonucleosides: Novel Drug Candidates for the Prevention and Treatment of Cytomegalovirus Diseases 417 Karen K. Biron, Kristjan S. Gudmundsson, and John C. Drach INDEX 435