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Non-nucleoside inhibitors of HCV NS5B polymerase. Part 1: Synthetic and computational exploration of the binding modes of benzothiadiazine and 1,4-benzothiazine HCV NS5b polymerase inhibitors |
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| Authors: | Robert T Hendricks Jay B Fell James F Blake John P Fischer John E Robinson Stacey R Spencer Peter J Stengel April L Bernacki Vincent JP Leveque Sophie Le Pogam Sonal Rajyaguru Isabel Najera John A Josey Jason R Harris Steven Swallow |
| Institution: | 1. Array BioPharma, Inc., 3200 Walnut Street, Boulder, CO 80301, USA;2. Roche Palo Alto, LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA |
| Abstract: | The importance of internal hydrogen bonding in a series of benzothiadiazine and 1,4-benzothiazine NS5b inhibitors has been explored. Computational analysis has been used to compare the protonated vs. anionic forms of each series and we demonstrate that activity against HCV NS5b polymerase is best explained using the anionic forms. The syntheses and structure–activity relationships for a variety of new analogs are also discussed. |
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