| Literature DB >> 24900473 |
Steven Harper1, John A McCauley2, Michael T Rudd2, Marco Ferrara1, Marcello DiFilippo1, Benedetta Crescenzi1, Uwe Koch1, Alessia Petrocchi1, M Katharine Holloway2, John W Butcher2, Joseph J Romano2, Kimberly J Bush2, Kevin F Gilbert2, Charles J McIntyre2, Kevin T Nguyen2, Emanuela Nizi1, Steven S Carroll2, Steven W Ludmerer2, Christine Burlein2, Jillian M DiMuzio2, Donald J Graham2, Carolyn M McHale2, Mark W Stahlhut2, David B Olsen2, Edith Monteagudo1, Simona Cianetti1, Claudio Giuliano1, Vincenzo Pucci1, Nicole Trainor2, Christine M Fandozzi2, Michael Rowley1, Paul J Coleman2, Joseph P Vacca2, Vincenzo Summa1, Nigel J Liverton2.
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.Entities:
Keywords: HCV; MK-5172; genotype 3a; hepatitis C; macrocycle; mutant enzymes
Year: 2012 PMID： 24900473 PMCID： PMC4025840 DOI： 10.1021/ml300017p
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345