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Cyclic amide bioisosterism: Strategic application to the design and synthesis of HCV NS5B polymerase inhibitors

✍ Scribed by Hanbiao Yang; Robert T. Hendricks; Nidhi Arora; Dov Nitzan; Calvin Yee; Matthew C. Lucas; Yanli Yang; Amy Fung; Sonal Rajyaguru; Seth F. Harris; Vincent J.P. Leveque; Julie Q. Hang; Sophie Le Pogam; Deborah Reuter; Gisele A. Tavares

Publisher: Elsevier Science
Year: 2010
Tongue: English
Weight: 653 KB
Volume: 20
Category: Article
ISSN: 0960-894X
DOI: 10.1016/j.bmcl.2010.06.008

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✦ Synopsis

Conformational modeling has been successfully applied to the design of cyclic bioisosteres used to replace a conformationally rigid amide bond in a series of thiophene carboxylate inhibitors of HCV NS5B polymerase. Select compounds were equipotent with the original amide series. Single-point mutant binding studies, in combination with inhibition structure-activity relationships, suggest this new series interacts at the Thumb-II domain of NS5B. Inhibitor binding at the Thumb-II site was ultimately confirmed by solving a crystal structure of 8b complexed with NS5B.

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