| Literature DB >> 20163176 |
John A McCauley1, Charles J McIntyre, Michael T Rudd, Kevin T Nguyen, Joseph J Romano, John W Butcher, Kevin F Gilbert, Kimberly J Bush, M Katharine Holloway, John Swestock, Bang-Lin Wan, Steven S Carroll, Jillian M DiMuzio, Donald J Graham, Steven W Ludmerer, Shi-Shan Mao, Mark W Stahlhut, Christine M Fandozzi, Nicole Trainor, David B Olsen, Joseph P Vacca, Nigel J Liverton.
Abstract
A new class of HCV NS3/4a protease inhibitors which contain a P2 to P4 macrocyclic constraint was designed using a molecular-modeling derived strategy. Exploration of the P2 heterocyclic region, the P2 to P4 linker, and the P1 side chain of this class of compounds via a modular synthetic strategy allowed for the optimization of enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 35b (vaniprevir, MK-7009), which is active against both the genotype 1 and genotype 2 NS3/4a protease enzymes and has good plasma exposure and excellent liver exposure in multiple species.Entities:
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Year: 2010 PMID： 20163176 DOI： 10.1021/jm9015526
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446