Novel bis(indolyl)maleimide pyridinophanes that are potent, selective inhibitors of glycogen synthase kinase-3

Bioorg Med Chem Lett. 2007 May 15;17(10):2863-8. doi: 10.1016/j.bmcl.2007.02.059. Epub 2007 Feb 25.

Abstract

Novel bis(indolyl)maleimide pyridinophanes 3, 9a, 9b, 10a, 10b, and 11 were prepared by cobalt-mediated [2+2+2] cycloaddition of an appropriate alpha,omega-diyne with an N,N-dialkylcyanamide. These macrocyclic heterophanes were found to be potent, selective inhibitors of glycogen synthase kinase-3beta. An X-ray structure of a co-crystal of GSK-3beta and 3 (IC(50)=3nM) depicts the hydrogen bonding and hydrophobic interactions in the ATP-binding pocket of this serine/threonine protein kinase.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Binding Sites
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacology*
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 / chemistry
  • Glycogen Synthase Kinase 3 beta
  • Hydrophobic and Hydrophilic Interactions
  • Maleimides / chemistry
  • Models, Molecular
  • Molecular Structure
  • Protein Conformation
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Maleimides
  • Pyridines
  • maleimide
  • Adenosine Triphosphate
  • Glycogen Synthase Kinase 3 beta
  • Glycogen Synthase Kinase 3