Investigation of glycine α-ketoamide HCV NS3 protease inhibitors: Effect of carboxylic acid isosteres

The design and synthesis of tetrapeptide-based α-ketoamides containing prime side acid isosteres HCV NS3 protease inhibitors are described. Tetrazole, sulfonic acid, and N-sulfonylcarboxamids were demonstrated to be efficient carboxylic acid replacements. Further optimization yielded a series of potent HCV NS3 protease inhibitors with IC50 of 0.020–0.060 μM.