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Cyclic amide bioisosterism: Strategic application to the design and synthesis of HCV NS5B polymerase inhibitors |
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| Authors: | Hanbiao Yang Robert T Hendricks Nidhi Arora Dov Nitzan Calvin Yee Matthew C Lucas Yanli Yang Amy Fung Sonal Rajyaguru Seth F Harris Vincent JP Leveque Julie Q Hang Sophie Le Pogam Deborah Reuter Gisele A Tavares |
| Institution: | 1. Medicinal Chemistry Department, Roche Palo Alto, LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, United States;2. Viral Diseases Discovery and Translational Area, Roche Palo Alto, LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, United States;3. Discovery Technologies X-ray Crystallography Group, Roche Palo Alto, LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, United States |
| 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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