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The discovery of a back-up to the hepatitis C virus NS3 protease inhibitor asunaprevir (2) is described. The objective of this work was the identification of a drug with antiviral properties and toxicology parameters similar to 2, but with a preclinical pharmacokinetic (PK) profile that was predictive of once-daily dosing. Critical to this discovery process was the employment of an ex vivo cardiovascular (CV) model which served to identify compounds that, like 2, were free of the CV liabilities that resulted in the discontinuation of BMS-605339 (1) from clinical trials. Structure-activity relationships (SARs) at each of the structural subsites in 2 were explored with substantial improvement in PK through modifications at the P1 site, while potency gains were found with small, but rationally designed structural changes to P4. Additional modifications at P3 were required to optimize the CV profile, and these combined SARs led to the discovery of BMS-890068 (29).

Asunaprevir (ASV; BMS-650032), a low nanomolar inhibitor of the hepatitis C virus (HCV) NS3 protease, is currently under development, in combination with other direct-acting antiviral (DAA) agents for the treatment of chronic HCV infection. Extensive nonclinical and pharmacokinetic studies have been conducted to characterize the ADME properties of ASV. ASV has a moderate to high clearance in preclinical species. In vitro reaction phenotyping studies demonstrated that the oxidative metabolism of ASV is primarily mediated via CYP3A4; however, studies in bile-duct cannulated rats and dogs suggest that biliary elimination may contribute to overall ASV clearance. ASV is shown to have hepatotropic disposition in all preclinical species tested (liver to plasma ratios >40). The translation of in vitro replicon potency to clinical viral load decline for a previous lead BMS-605339 was leveraged to predict a human dose of 2 mg BID for ASV. Clinical drug-drug interaction (DDI) studies have shown that at therapeutically relevant concentrations of ASV the potential for a DDI is minimal. The need for an interferon free treatment combined with ASV's initial clinical trial data support development of ASV as part of a fixed dose combination for the treatment of patients chronically infected with HCV genotype 1., (© 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.)

The discovery of BMS-605339 (35), a tripeptidic inhibitor of the NS3/4A enzyme, is described. This compound incorporates a cyclopropylacylsulfonamide moiety that was designed to improve the potency of carboxylic acid prototypes through the introduction of favorable nonbonding interactions within the S1' site of the protease. The identification of 35 was enabled through the optimization and balance of critical properties including potency and pharmacokinetics (PK). This was achieved through modulation of the P2* subsite of the inhibitor which identified the isoquinoline ring system as a key template for improving PK properties with further optimization achieved through functionalization. A methoxy moiety at the C6 position of this isoquinoline ring system proved to be optimal with respect to potency and PK, thus providing the clinical compound 35 which demonstrated antiviral activity in HCV-infected patients.

The discovery of asunaprevir (BMS-650032, 24) is described. This tripeptidic acylsulfonamide inhibitor of the NS3/4A enzyme is currently in phase III clinical trials for the treatment of hepatitis C virus infection. The discovery of 24 was enabled by employing an isolated rabbit heart model to screen for the cardiovascular (CV) liabilities (changes to HR and SNRT) that were responsible for the discontinuation of an earlier lead from this chemical series, BMS-605339 (1), from clinical trials. The structure-activity relationships (SARs) developed with respect to CV effects established that small structural changes to the P2* subsite of the molecule had a significant impact on the CV profile of a given compound. The antiviral activity, preclincial PK profile, and toxicology studies in rat and dog supported clinical development of BMS-650032 (24).