Novel indolylindazolylmaleimides as inhibitors of protein kinase C-β: Synthesis, biological activity, and cardiovascular safety

HC Zhang, CK Derian, DF McComsey…

Index: Zhang, Han-Cheng; Derian, Claudia K.; McComsey, David F.; White, Kimberly B.; Ye, Hong; Hecker, Leonard R.; Li, Jian; Addo, Michael F.; Croll, Diane; Eckardt, Annette J.; Smith, Charles E.; Li, Quan; Cheung, Wai-Man; Conway, Bruce R.; Emanuel, Stuart; Demarest, Keith T.; Andrade-Gordon, Patricia; Damiano, Bruce P.; Maryanoff, Bruce E. Journal of Medicinal Chemistry, 2005 , vol. 48, # 6 p. 1725 - 1728

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Citation Number: 64

Abstract

Novel indolylindazolylmaleimides were synthesized and examined for kinase inhibition. We identified low-nanomolar inhibitors of PKC-β with good to excellent selectivity vs other PKC isozymes and GSK-3β. In a cell-based functional assay, 8f and 8i effectively blocked IL-8 release induced by PKC-βII (IC50= 20-25 nM). In cardiovascular safety assessment, representative lead compounds bound to the hERG channel with high affinity, potently ...

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