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Non-nucleoside inhibitors of HCV polymerase NS5B. Part 4: Structure-based design, synthesis, and biological evaluation of benzo[d]isothiazole-1,1-dioxides

2009; Elsevier BV; Volume: 19; Issue: 19 Linguagem: Inglês

10.1016/j.bmcl.2009.08.022

1464-3405

Javier de Vicente, R. Hendricks, David B. Smith, Jay B. Fell, John P. Fischer, Stacey R. Spencer, Peter J. Stengel, Peter J. Mohr, John Robinson, James F. Blake, Ramona Hilgenkamp, Calvin Yee, George M. Adjabeng, Todd R. Elworthy, Jimmy Li, Beihan Wang, Joe T. Bamberg, Seth F. Harris, April Wong, Vincent Lévêque, Isabel Nájera, Sophie Le Pogam, Sonal Rajyaguru, Gloria Ao-Ieong, L. А. Alexandrova, Susan Larrabee, Michael Brandl, Andrew J. Briggs, Sunil Sukhtankar, Robert Farrell,

Biochemical and Molecular Research

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.