|
|||||
|
|
Cyclic amide bioisosterism: Strategic application to the design and synthesis of HCV NS5B polymerase inhibitors |
|
| 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 J.P. Leveque Julie Q. Hang Sophie Le Pogam Deborah Reuter Gisele A. Tavares |
| Affiliation: | 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. |
| Keywords: | |
| 本文献已被 ScienceDirect 等数据库收录！ | |