Optimization of Thienopyrrole-Based Finger-Loop Inhibitors of the Hepatitis C Virus NS5B Polymerase

✍ Scribed by Jose Ignacio Martin Hernando; Jesus Maria Ontoria; Savina Malancona; Barbara Attenni; Fabrizio Fiore; Fabio Bonelli; Uwe Koch; Stefania Di Marco; Stefania Colarusso; Simona Ponzi; Nadia Gennari; Sue Ellen Vignetti; Maria del Rosario Rico Ferreira; Jörg Habermann; Michael Rowley; Frank Narjes

• Book ID: 102805351
• Publisher: John Wiley and Sons
• Year: 2009
• Tongue: English
• Weight: 520 KB
• Volume: 4
• Category: Article
• ISSN: 1860-7179
• DOI: 10.1002/cmdc.200900184

✦ Synopsis

Abstract

Infections caused by the hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The NS5B polymerase of HCV is responsible for the replication of viral RNA and has been a prime target in the search for novel treatment options. We had discovered allosteric finger‐loop inhibitors based on a thieno[3,2‐b]pyrrole scaffold as an alternative to the related indole inhibitors. Optimization of the thienopyrrole series led to several N__‐acetamides with submicromolar potency in the cell‐based replicon assay, but they lacked oral bioavailability in rats. By linking the N4‐position to the__ ortho__‐position of the C5‐aryl group, we were able to identify the tetracyclic thienopyrrole 40, which displayed a favorable pharmacokinetic profile in rats and dogs and is equipotent with recently disclosed finger‐loop inhibitors based on an indole scaffold.__