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

  • J Med Chem. 2005 Mar 24;48(6):1725-8. doi: 10.1021/jm049478u.
Han-Cheng Zhang  1 ,  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
Affiliations
  • 1. Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, Spring House, Pennsylvania 19477-0776, USA. [email protected]
PMID: 15771419 DOI: 10.1021/jm049478u
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.