Inhibitors of hepatitis C virus NS3·4A protease. Part 3: P2 proline variants

We recently described the identification of an optimized α-ketoamide warhead for our series of HCV NS3·4A inhibitors. We report herein a series of HCV protease inhibitors incorporating 3-alkyl-substituted prolines in P2. These compounds show exceptional enzymatic and cellular potency given their relatively small size. The marked enhancement of activity of these 3-substituted proline derivatives relative to previously reported 4-hydroxyproline derivatives constitutes additional evidence for the importance of the S2 binding pocket as the defining pharmacophore for inhibition of the NS3·4A enzyme.