Non-nucleoside inhibitors of HCV polymerase NS5B. Part 4: Structure-based design,synthesis, and biological evaluation of benzo[d]isothiazole-1,1-dioxides |
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Authors: | Javier de Vicente Robert T. Hendricks David B. Smith Jay B. Fell John Fischer Stacey R. Spencer Peter J. Stengel Peter Mohr John E. Robinson James F. Blake Ramona K. Hilgenkamp Calvin Yee George Adjabeng Todd R. Elworthy Jim Li Beihan Wang Joe T. Bamberg Seth F. Harris April Wong Vincent J.P. Leveque Robert Farrell |
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Affiliation: | 1. Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA;2. Array BioPharma Inc, 3200 Walnut Street, Boulder, CO 80301, USA |
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Abstract: | A series of benzo[d]isothiazole-1,1-dioxides were designed and evaluated as inhibitors of HCV polymerase NS5B. Structure-based design led to the incorporation of a high affinity methyl sulfonamide group. Structure–activity relationship (SAR) studies of this series revealed analogues with submicromolar potencies in the HCV replicon assay and moderate pharmacokinetic properties. SAR studies combined with structure based drug design focused on the sulfonamide region led to a novel and potent cyclic analogue. |
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