Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor
Steven J. Harper(IRBM Science Park), John A. McCauley(IRBM Science Park), Michael T. Rudd(Merck & Co., Inc., Rahway, NJ, USA (United States)), Marco Ferrara(United States Military Academy), Marcello DiFilippo(IRBM Science Park), Benedetta Crescenzi(Merck & Co., Inc., Rahway, NJ, USA (United States)), Uwe Koch(United States Military Academy), Alessia Petrocchi(IRBM Science Park), M. Katharine Holloway(Merck & Co., Inc., Rahway, NJ, USA (United States)), John W. Butcher(United States Military Academy), Joseph J. Romano(United States Military Academy), Kimberly J. Bush(Merck & Co., Inc., Rahway, NJ, USA (United States)), Kevin F. Gilbert(IRBM Science Park), Charles McIntyre(Merck & Co., Inc., Rahway, NJ, USA (United States)), Kevin T. Nguyen(United States Military Academy), Emanuela Nizi(Merck & Co., Inc., Rahway, NJ, USA (United States)), Steven S. Carroll(IRBM Science Park), Steven W. Ludmerer(United States Military Academy), Christine Burlein(Merck & Co., Inc., Rahway, NJ, USA (United States)), Jillian DiMuzio(United States Military Academy), Donald J. Graham(United States Military Academy), Carolyn McHale(Merck & Co., Inc., Rahway, NJ, USA (United States)), Mark W. Stahlhut(Merck & Co., Inc., Rahway, NJ, USA (United States)), David B. Olsen(Merck & Co., Inc., Rahway, NJ, USA (United States)), Edith Monteagudo(Merck & Co., Inc., Rahway, NJ, USA (United States)), Simona Cianetti(United States Military Academy), Claudio Giuliano(Merck & Co., Inc., Rahway, NJ, USA (United States)), Vincenzo Pucci(Merck & Co., Inc., Rahway, NJ, USA (United States)), Nicole Trainor(Merck & Co., Inc., Rahway, NJ, USA (United States)), Christine Fandozzi(Merck & Co., Inc., Rahway, NJ, USA (United States)), Michael Rowley(United States Military Academy), Paul J. Coleman(United States Military Academy), Joseph P. Vacca(Merck & Co., Inc., Rahway, NJ, USA (United States)), Vincenzo Summa(United States Military Academy), Nigel J. Liverton(United States Military Academy)
Cited by 201Open Access
Abstract
A new class of HCV NS3/4a protease inhibitors containing a P2 to P4 macrocyclic constraint was designed using a molecular modeling-derived strategy. Building on the profile of previous clinical compounds and exploring the P2 and linker regions of the series allowed for optimization of broad genotype and mutant enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 15 (MK-5172), which is active against genotype 1-3 NS3/4a and clinically relevant mutant enzymes and has good plasma exposure and excellent liver exposure in multiple species.
Related Papers
No related papers found
Powered by citation graph analysis