2. Academic Validation
  3. Novel indolylindazolylmaleimides as inhibitors of protein kinase C-beta: synthesis, biological activity, and cardiovascular safety

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

Affiliation

  • 1 Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, Spring House, Pennsylvania 19477-0776, USA. hzhang@prdus.jnj.com
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.

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