P4 and P1′ optimization of bicycloproline P2 bearing tetrapeptidyl α-ketoamides as HCV protease inhibitors

We describe herein the design, synthesis, and antiviral activity of a series of P4 modified tetrapeptidyl α-ketoamides as HCV protease inhibitors. The most promising analog identified through this SAR, 5a, 5c, and 5e demonstrated excellent enzyme inhibitory potency, enzyme selectivity, cellular activity, and acceptable therapeutic indexes.