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Optimization of thienopyrrole-based finger-loop inhibitors of the hepatitis C virus NS5B polymerase. | LitMetric

Optimization of thienopyrrole-based finger-loop inhibitors of the hepatitis C virus NS5B polymerase.

ChemMedChem

Department of Medicinal Chemistry, Istituto di Ricerche di Biologia Molecolare P. Angeletti S.p.A. Merck Sharp & Dohme Research Laboratories Rome, Via Pontina km 30,600, 00040 Pomezia (Italy).

Published: October 2009

AI Article Synopsis

Article 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.

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Source
http://dx.doi.org/10.1002/cmdc.200900184DOI Listing

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