Novel P2-P4 macrocyclic inhibitors of HCV NS3/4A protease by P3 succinamide fragment depeptidization strategy.

By Pompei, Marco; Di Francesco, Maria Emilia; Pesci, Silvia; Koch, Uwe; Vignetti, Sue Ellen; Veneziano, Maria; Pace, Paola; Summa, Vincenzo
From Bioorganic & Medicinal Chemistry Letters (2010), 20(1), 168-174. Language: English, Database: CAPLUS, DOI:10.1016/j.bmcl.2009.11.005

Hepatitis C represents a serious worldwide health-care problem. Recently, we have disclosed a novel class of P2-P4 macrocyclic inhibitors of NS3/4A protease contg. a carbamate functionality as capping group at the P3 N-terminus. Herein we report our work aimed at further depeptidizing the P3 region by replacement of the urethane function with a succinamide motif. This peptidomimetic approach has led to the discovery of novel P2-P4 macrocyclic inhibitors of HCV NS3/4A protease with sub-nanomolar enzyme affinities. In addn. to being potent inhibitors of HCV subgenomic replication, optimized analogs within this series have also presented attractive PK properties and showed promising liver levels in rat following oral administration.