Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor.
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ABSTRACT:
SUBMITTER: Harper S
PROVIDER: S-EPMC4025840 | biostudies-other | 2012 Apr
REPOSITORIES: biostudies-other
Publications
Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor.
Harper Steven S McCauley John A JA Rudd Michael T MT Ferrara Marco M DiFilippo Marcello M Crescenzi Benedetta B Koch Uwe U Petrocchi Alessia A Holloway M Katharine MK Butcher John W JW Romano Joseph J JJ Bush Kimberly J KJ Gilbert Kevin F KF McIntyre Charles J CJ Nguyen Kevin T KT Nizi Emanuela E Carroll Steven S SS Ludmerer Steven W SW Burlein Christine C DiMuzio Jillian M JM Graham Donald J DJ McHale Carolyn M CM Stahlhut Mark W MW Olsen David B DB Monteagudo Edith E Cianetti Simona S Giuliano Claudio C Pucci Vincenzo V Trainor Nicole N Fandozzi Christine M CM Rowley Michael M Coleman Paul J PJ Vacca Joseph P JP Summa Vincenzo V Liverton Nigel J NJ
ACS medicinal chemistry letters 20120302 4
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 genotyp ...[more]
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