Herein, the design, synthesis and inhibitory potency of a series of novel hepatitis C virus (HCV) NS3 protease inhibitors are presented. These inhibitors are based on a 2(1H)-pyrazinone P3 scaffold in combination with either a P2 phenylglycine or a glycine, and they were evaluated on the wild type as well as on two resistant variants of the enzyme, A156T and D168V. Molecular modelling suggested that the aromatic side-chain of the P2 phenylglycine occupies the same space as the substituent in position 6 on the pyrazinone core. The versatile synthetic route applied for the pyrazinone synthesis made a switch between the two positions easily feasible, resulting in phenyl- or benzyl substituted pyrazinones and leaving glycine as the P2 residue. Of several P1-P1' residues evaluated, an aromatic P1-P1' scaffold was found superior in combination with the new P3-P2 building block. As a result, an entirely new type of achiral and rigidified inhibitors was discovered, with the best of the novel inhibitors having fourfold improved potency compared to the corresponding tripeptide lead. We consider these achiral inhibitors highly suitable as starting points for further optimization.
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