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Discovery of Novel Allosteric HCV NS5B Inhibitors. 2. Lactam-Containing Thiophene Carboxylates. | LitMetric

AI Article Synopsis

Article Abstract

Lomibuvir () is a non-nucleoside, allosteric inhibitor of the hepatitis C virus NS5B polymerase with demonstrated clinical efficacy. Further development efforts within this class of inhibitor focused on improving the antiviral activity and physicochemical and pharmacokinetic properties. Recently, we reported the development of this series, leading to compound , a molecule with comparable potency and an improved physicochemical profile relative to . Further exploration of the amino amide-derived side chain led to a series of lactam derivatives, inspired by the X-ray crystal structure of related thiophene carboxylate inhibitors. This series, exemplified by , provided 3-5-fold improvement in potency against HCV replication, as measured by replicon assays. The synthesis, structure-activity relationships, ADME characterization, and evaluation of this novel series are discussed.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5304295PMC
http://dx.doi.org/10.1021/acsmedchemlett.6b00479DOI Listing

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