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

• Published in: ACS medicinal chemistry letters Vol. 3; no. 4; pp. 332 - 336
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 12.04.2012
• Subjects: Letter; MK-5172; genotype 3a; macrocycle; HCV; hepatitis C; mutant enzymes
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/ml300017p

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.