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

Bioorg Med Chem Lett. 2010 Aug 1;20(15):4614-9. doi: 10.1016/j.bmcl.2010.06.008.

Hanbiao Yang ¹, 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

Affiliations

Affiliation

1 Medicinal Chemistry Department, Roche Palo Alto, LLC, Palo Alto, CA 94304, USA. [email protected]

PMID: 20584604 DOI: 10.1016/j.bmcl.2010.06.008

Abstract

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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