Discovery of vaniprevir (MK-7009), a macrocyclic hepatitis C virus NS3/4a protease inhibitor.
Basic Information
ID: ALA1157609
Journal: J Med Chem
Title: Discovery of vaniprevir (MK-7009), a macrocyclic hepatitis C virus NS3/4a protease inhibitor.
Authors: McCauley JA, McIntyre CJ, Rudd MT, Nguyen KT, Romano JJ, Butcher JW, Gilbert KF, Bush KJ, Holloway MK, Swestock J, Wan BL, Carroll SS, DiMuzio JM, Graham DJ, Ludmerer SW, Mao SS, Stahlhut MW, Fandozzi CM, Trainor N, Olsen DB, Vacca JP, Liverton NJ.
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.
CiteXplore: 20163176
DOI: 10.1021/jm9015526
Patent ID: ┄