Acyclic N-(azacycloalkyl)bisindolylmaleimides: isozyme selective inhibitors of PKCbeta

Bioorg Med Chem Lett. 2003 Jun 2;13(11):1857-9. doi: 10.1016/s0960-894x(03)00286-5.

Abstract

The synthesis and structure-activity relationship (SAR) trends of a new class of N-(azacycloalkyl)bisindolylmaleimides 1, acyclic derivatives of staurosporine, is described. The representative compound for this series (1e) exhibits an IC(50) of 40-50 nM against the human PKCbeta(1) and PKCbeta(2) isozymes and selectively inhibits the PKCbeta isozymes in comparison to other PKC isozymes (alpha, gamma, delta, epsilon, lambda, and eta). The series is also kinase selective for PKC in comparison to other ATP-dependent kinases. A comparison of the PKC isozyme and kinase activity of the series is made to the kinase inhibitor staurosporine.

Publication types

  • Comparative Study

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Indoles / chemistry*
  • Indoles / pharmacology*
  • Inhibitory Concentration 50
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / genetics
  • Maleimides / chemistry*
  • Maleimides / pharmacology*
  • Protein Kinase C / antagonists & inhibitors*
  • Protein Kinase C / genetics
  • Protein Kinase C beta
  • Protein Kinase Inhibitors
  • Protein Kinases / metabolism
  • Rats
  • Staurosporine / analogs & derivatives
  • Staurosporine / pharmacology
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Indoles
  • Isoenzymes
  • Maleimides
  • Protein Kinase Inhibitors
  • Adenosine Triphosphate
  • Protein Kinases
  • Protein Kinase C
  • Protein Kinase C beta
  • Staurosporine
  • bisindolylmaleimide