Potent benzimidazole sulfonamide protein tyrosine phosphatase 1B inhibitors containing the heterocyclic (S)-isothiazolidinone phosphotyrosine mimetic

…, W Zhu, ML Crawley, B Glass, P Polam…

Index: Combs, Andrew P.; Zhu, Wenyu; Crawley, Matthew L.; Glass, Brian; Polam, Padmaja; Sparks, Richard B.; Modi, Dilip; Takvorian, Amy; McLaughlin, Erin; Yue, Eddy W.; Wasserman, Zelda; Bower, Michael; Wei, Min; Rupar, Mark; Ala, Paul J.; Reid, Brian M.; Ellis, Dawn; Gonneville, Lucie; Emm, Thomas; Taylor, Nancy; Yeleswaram, Swamy; Li, Yanlong; Wynn, Richard; Burn, Timothy C.; Hollis, Gregory; Liu, Phillip C. C.; Metcalf, Brian Journal of Medicinal Chemistry, 2006 , vol. 49, # 13 p. 3774 - 3789

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Citation Number: 78

Abstract

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 ...