Bioorg Med Chem Lett. 2009 Oct 1;19(19):5652-6. Epub 2009 Aug 8.

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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Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA. javier.devicente@roche.com

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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Structures reported by this article

Hepatitis C Virus Polymerase Ns5b With Saccharin Inhibitor 1

PDB: 3H5U

Source: Hepatitis C virus (isolate BK)

Method: X-Ray Diffraction

Resolution: 1.95 Å

See all 2 structures...

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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.

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