1. Non-nucleoside inhibitors of HCV polymerase NS5B. Part 4: structure-based design, synthesis, and biological evaluation of benzo[d]isothiazole-1,1-dioxides.
- Author
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de Vicente J, Hendricks RT, Smith DB, Fell JB, Fischer J, Spencer SR, Stengel PJ, Mohr P, Robinson JE, Blake JF, Hilgenkamp RK, Yee C, Adjabeng G, Elworthy TR, Li J, Wang B, Bamberg JT, Harris SF, Wong A, Leveque VJ, Najera I, Le Pogam S, Rajyaguru S, Ao-Ieong G, Alexandrova L, Larrabee S, Brandl M, Briggs A, Sukhtankar S, and Farrell R
- Subjects
- Animals, Antiviral Agents chemistry, Antiviral Agents pharmacokinetics, Binding Sites, Crystallography, X-Ray, Haplorhini, Rats, Structure-Activity Relationship, Thiazoles chemical synthesis, Thiazoles pharmacokinetics, Viral Nonstructural Proteins metabolism, Antiviral Agents chemical synthesis, Hepacivirus drug effects, Thiazoles chemistry, Viral Nonstructural Proteins antagonists & inhibitors
- 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.
- Published
- 2009
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