American Chemical Society
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Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor

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journal contribution
posted on 2016-02-21, 14:48 authored by Steven Harper, John A. McCauley, Michael T. Rudd, Marco Ferrara, Marcello DiFilippo, Benedetta Crescenzi, Uwe Koch, Alessia Petrocchi, M. Katharine Holloway, John W. Butcher, Joseph J. Romano, Kimberly J. Bush, Kevin F. Gilbert, Charles J. McIntyre, Kevin T. Nguyen, Emanuela Nizi, Steven S. Carroll, Steven W. Ludmerer, Christine Burlein, Jillian M. DiMuzio, Donald J. Graham, Carolyn M. McHale, Mark W. Stahlhut, David B. Olsen, Edith Monteagudo, Simona Cianetti, Claudio Giuliano, Vincenzo Pucci, Nicole Trainor, Christine M. Fandozzi, Michael Rowley, Paul J. Coleman, Joseph P. Vacca, Vincenzo Summa, Nigel J. Liverton
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.