Discovery of SCH446211 (SCH6): A new ketoamide inhibitor of the HCV NS3 serine protease and HCV subgenomic RNA replication

Introduction of various modified prolines at P-2 and optimization of the P-1 side chain led to the discovery of SCH6 (24, Table 2), a potent ketoamide inhibitor of the HCV NS3 serine protease. In addition to excellent enzyme potency (K-i* = 3.8 nM), 24 was also found to be a potent inhibitor of HCV subgenomic RNA replication with IC50 and IC90 of 40 and 100 nM, respectively. Recently, antiviral activity of 24 was demonstrated with inhibition of the full-length genotype 2a HCV genome. In addition, 24 was found to restore the responsiveness of the interferon regulatory factor 3 (IRF-3) in cells containing HCV RNA replicons.