Highly potent non-peptidic inhibitors of the HCV NS3/NS4A serine protease

Abstract Screening of a diverse set of bisbenzimidazoles for inhibition of the hepatitis C virus (HCV) serine protease NS3/NS4A led to the identification of a potent Zn 2+ -dependent inhibitor ( 1 ). Optimization of this screening hit afforded a 10-fold more potent inhibitor ( 46 ) under Zn 2+ conditions ( K i =27 nM). This compound ( 46 ) binds also to NS3/NS4A in a Zn 2+ independent fashion ( K i =1 μM). The SAR of this class of compounds under Zn 2+ conditions is highly divergent compared to the SAR in the absence of Zn 2+ , suggesting two distinct binding modes.