Discovery of a Potent Acyclic, Tripeptidic, Acyl Sulfonamide Inhibitor of Hepatitis C Virus NS3 Protease as a Back-up to Asunaprevir with the Potential for Once-Daily Dosing

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).