Referenced in: none

Automatically associated channels: Kv11.1

Title: Novel indolylindazolylmaleimides as inhibitors of protein kinase C-beta: synthesis, biological activity, and cardiovascular safety.

Authors: Han-Cheng Zhang, Claudia K Derian, David F McComsey, Kimberly B White, Hong Ye, Leonard R Hecker, Jian Li, Michael F Addo, Diane Croll, Annette J Eckardt, Charles E Smith, Quan Li, Wai-Man Cheung, Bruce R Conway, Stuart Emanuel, Keith T Demarest, Patricia Andrade-Gordon, Bruce P Damiano, Bruce E Maryanoff

Journal, date & volume: J. Med. Chem., 2005 Mar 24 , 48, 1725-8

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/15771419

Abstract
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.