Discovery of MK-5172, a macrocyclic hepatitis C virus NS3/4a protease inhibitor

…, M Ferrara, M DiFilippo, B Crescenzi…

Index: Harper, Steven; McCauley, John A.; Rudd, Michael T.; Ferrara, Marco; DiFilippo, Marcello; Crescenzi, Benedetta; Koch, Uwe; Petrocchi, Alessia; Holloway, M. Katharine; Butcher, John W.; Romano, Joseph J.; Bush, Kimberly J.; Gilbert, Kevin F.; McIntyre, Charles J.; Nguyen, Kevin T.; Nizi, Emanuela; Carroll, Steven S.; Ludmerer, Steven W.; Burlein, Christine; Dimuzio, Jillian M.; Graham, Donald J.; McHale, Carolyn M.; Stahlhut, Mark W.; Olsen, David B.; Monteagudo, Edith; Cianetti, Simona; Giuliano, Claudio; Pucci, Vincenzo; Trainor, Nicole; Fandozzi, Christine M.; Rowley, Michael; Coleman, Paul J.; Vacca, Joseph P.; Summa, Vincenzo; Liverton, Nigel J. ACS Medicinal Chemistry Letters, 2012 , vol. 3, # 4 p. 332 - 336

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Citation Number: 68

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 ...