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Potent Benzimidazole Sulfonamide Protein Tyrosine Phosphatase 1B Inhibitors Containing the Heterocyclic (S)-Isothiazolidinone Phosphotyrosine Mimetic

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journal contribution
posted on 29.06.2006, 00:00 by Andrew P. Combs, Wenyu Zhu, Matthew L. Crawley, Brian Glass, Padmaja Polam, Richard B. Sparks, Dilip Modi, Amy Takvorian, Erin McLaughlin, Eddy W. Yue, Zelda Wasserman, Michael Bower, Min Wei, Mark Rupar, Paul J. Ala, Brian M. Reid, Dawn Ellis, Lucie Gonneville, Thomas Emm, Nancy Taylor, Swamy Yeleswaram, Yanlong Li, Richard Wynn, Timothy C. Burn, Gregory Hollis, Phillip C. C. Liu, Brian Metcalf
Potent nonpeptidic benzimidazole sulfonamide inhibitors of protein tyrosine phosphatase 1B (PTP1B) were derived from the optimization of a tripeptide containing the novel (S)-isothiazolidinone ((S)-IZD) phosphotyrosine (pTyr) mimetic. An X-ray cocrystal structure of inhibitor 46/PTP1B at 1.8 Å resolution demonstrated that the benzimidazole sulfonamides form a bidentate H bond to Asp48 as designed, although the aryl group of the sulfonamide unexpectedly interacts intramolecularly in a pi-stacking manner with the benzimidazole. The ortho substitution to the (S)-IZD on the aryl ring afforded low nanomolar enzyme inhibitors of PTP1B that also displayed low caco-2 permeability and cellular activity in an insulin receptor (IR) phosphorylation assay and an Akt phosphorylation assay. The design, synthesis, and SAR of this novel series of benzimidazole sulfonamide containing (S)-IZD inhibitors of PTP1B are presented herein.

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