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

Autor:	Hong Ye, Annette J. Eckardt, Charles E. Smith, Han-Cheng Zhang, David F. McComsey, Bruce E. Maryanoff, Wai-man Cheung, Bruce P. Damiano, Claudia K. Derian, Keith T. Demarest, Stuart Emanuel, Patricia Andrade-Gordon, Kimberly White, Diane R. Croll, Bruce R. Conway, Leonard R. Hecker, Michael F. Addo, Jian Li, Quan Li
Rok vydání:	2004
Předmět:	Models Molecular ERG1 Potassium Channel Indazoles Indoles Patch-Clamp Techniques Guinea Pigs hERG Protein Kinase C beta Pharmacology Cell Line Maleimides Glycogen Synthase Kinase 3 Structure-Activity Relationship GSK-3 Drug Discovery Potassium Channel Blockers Animals Humans GSK3B Protein Kinase C Protein kinase C Glycogen Synthase Kinase 3 beta biology Chemistry Interleukin-8 Biological activity Ether-A-Go-Go Potassium Channels Potassium channel Isoenzymes Long QT Syndrome Biochemistry Potassium Channels Voltage-Gated Enzyme inhibitor biology.protein Molecular Medicine
Zdroj:	Journal of Medicinal Chemistry. 48:1725-1728
ISSN:	1520-4804 0022-2623
Popis:	Novel indolylindazolylmaleimides were synthesized and examined for kinase inhibition. We identified low-nanomolar inhibitors of PKC-beta with good to excellent selectivity vs other PKC isozymes and GSK-3beta. In a cell-based functional assay, 8f and 8i effectively blocked IL-8 release induced by PKC-betaII (IC(50) = 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 QT(c) in guinea pigs.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::58229b9216bbae205d9250ebc6834928 https://doi.org/10.1021/jm049478u Zobrazit plný text záznamu