We describe herein tetrapeptidyl α-ketoamide 4A based systematic P1 modifications alone or/and in combination with further P1; variations. These SAR efforts led to the discovery of a number of potent and selective HCV NS3 protease inhibitors such as 4B, 9, and 12 endowed with impressive cellular activity as measured in the replicon assay and very good therapeutic indexes. On the basis of its overall profile, compound 4B (VX-950) has been selected for human clinical trials.
Keywords: hcv infection, ns3 protease, enzyme inhibition, replicon assay, cytotoxicity, alpha-ketoamide
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