Combinations of mechanistically orthogonal direct acting antiviral agents have achieved high cure rates in the treatment of genotype 1 hepatitis C virus infection. As part of the evolution of therapy, we sought pan-genotypic HCV NS3 inhibitors that could be used in combination therapy. In this presentation, we will describe the discovery of BMS-986144, a potent HCV NS3 protease inhibitor that demonstrates potent pan-genotypic antiviral activity in vitro. This molecule incorporates P3 and P1 into a macrocycle ring that is combined with specific manipulation of substitution patterns of the tether to achieve high potency across genotypes and toward resistant variants. The pharmacokinetic profile of BMS-986144 in three preclinical species predicts the potential for once daily administration in combination therapy. The principles behind the design of BMS-986144 will be described in detail along with preclinical profiling data that characterize this compound as a 2nd generation protease inhibitor.

Second-generation inhibitors of the hepatitis C virus NS3/4A protease: Discovery of BMS-986144 with pan-genotypic antiviral activity

254th National Meeting (2017)

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