Identification of 2-(4-pyridyl)thienopyridinones as GSK-3β inhibitors

Bioorg Med Chem Lett. 2011 Aug 15;21(16):4823-7. doi: 10.1016/j.bmcl.2011.06.050. Epub 2011 Jun 29.

Abstract

The discovery of a novel series of 2-(4-pyridyl)thienopyridinone GSK-3β inhibitors is reported. X-ray crystallography reveals its binding mode and enables rationalization of the SAR. The initial optimization of the template for improved cellular activity and predicted CNS penetration is also presented.

MeSH terms

  • Cell Line
  • Central Nervous System / drug effects
  • Central Nervous System / metabolism
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Discovery
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Permeability / drug effects
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyridones / chemical synthesis
  • Pyridones / chemistry
  • Pyridones / pharmacology*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Thiophenes / chemical synthesis
  • Thiophenes / chemistry
  • Thiophenes / pharmacology*

Substances

  • Protein Kinase Inhibitors
  • Pyridones
  • Thiophenes
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Glycogen Synthase Kinase 3