Phenethyl Amides as Novel Noncovalent Inhibitors of Hepatitis C Virus NS3/4A Protease: Discovery, Initial SAR, and Molecular Modeling

The discovery of novel, reversible and competitive tripeptide inhibitors of the Hepatitis C virus NS3/4A serine protease is described. These inhibitors are characterized by the presence of a C-terminal phenethyl amide group, which extends into the prime side of the enzyme. Initial SAR together with molecular modeling and data from site-directed mutagenesis suggest an interaction of the phenethyl amide group with Lys-136.