Novel Indolylindazolylmaleimides as Inhibitors of Protein Kinase C-β: Synthesis, Biological Activity, and Cardiovascular Safety

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 (...

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Veröffentlicht in:	Journal of medicinal chemistry 2005-03, Vol.48 (6), p.1725-1728
Hauptverfasser:	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
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Cell Line ERG1 Potassium Channel Ether-A-Go-Go Potassium Channels Glycogen Synthase Kinase 3 - antagonists & inhibitors Glycogen Synthase Kinase 3 - chemistry Glycogen Synthase Kinase 3 beta Guinea Pigs Humans Indazoles - chemical synthesis Indazoles - pharmacology Indazoles - toxicity Indoles - chemical synthesis Indoles - pharmacology Indoles - toxicity Interleukin-8 - metabolism Isoenzymes - antagonists & inhibitors Isoenzymes - chemistry Long QT Syndrome - chemically induced Maleimides - chemical synthesis Maleimides - pharmacology Maleimides - toxicity Models, Molecular Patch-Clamp Techniques Potassium Channel Blockers - chemical synthesis Potassium Channel Blockers - chemistry Potassium Channel Blockers - pharmacology Potassium Channels, Voltage-Gated - drug effects Potassium Channels, Voltage-Gated - metabolism Protein Kinase C - antagonists & inhibitors Protein Kinase C - chemistry Protein Kinase C beta Structure-Activity Relationship
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Zusammenfassung:	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 inhibited ion current in a patch-clamp experiment, and caused a dose-dependent increase of QTc in guinea pigs.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm049478u