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

Bioorganic & Medicinal Chemistry Letters
Marco PompeiVincenzo Summa

Abstract

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 containing 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 addition to being potent inhibitors of HCV subgenomic replication, optimized analogues within this series have also presented attractive PK properties and showed promising liver levels in rat following oral administration.

References

Aug 17, 2002·Protein Expression and Purification·Anton PoliakovU Helena Danielson
Oct 31, 2002·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·UNKNOWN National Institutes of Health
Aug 19, 2005·Nature·Raffaele De Francesco, Giovanni Migliaccio
Jan 1, 2009·Nature Reviews. Drug Discovery
Oct 21, 2009·Antimicrobial Agents and Chemotherapy·Nigel J LivertonJoseph P Vacca

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Citations

Nov 8, 2011·Drug Discovery Today·Hongmao SunAnders Wallqvist
Aug 12, 2016·Journal of the American Chemical Society·Djadé I SoumanaCelia A Schiffer

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