Discovery of novel 2-(3-phenylpiperazin-1-yl)-pyrimidin-4-ones as glycogen synthase kinase-3β inhibitors

Bioorg Med Chem Lett. 2017 Aug 15;27(16):3726-3732. doi: 10.1016/j.bmcl.2017.06.078. Epub 2017 Jul 5.

Abstract

We herein describe the results of further evolution of glycogen synthase kinase (GSK)-3β inhibitors from our promising compounds containing a 2-phenylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3β inhibitors. SAR studies focused on the phenyl moiety revealed that a 4-fluoro-2-methoxy group afforded potent inhibitory activity toward GSK-3β. Based on docking studies, new hydrogen bonding between the nitrogen atom of the piperazine moiety and the oxygen atom of the main chain of Gln185 has been indicated, which may contribute to increased activity compared with that of the corresponding phenylmorpholine analogues. Effect of the stereochemistry of the phenylpiperazine moiety is also discussed.

Keywords: Alzheimer’s disease; glycogen synthase kinase-3; phenylpiperazine.

MeSH terms

  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Piperazines / chemical synthesis
  • Piperazines / chemistry
  • Piperazines / pharmacology*
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidinones / chemical synthesis
  • Pyrimidinones / chemistry
  • Pyrimidinones / pharmacology*
  • Structure-Activity Relationship

Substances

  • 2-(3-phenylpiperazin-1-yl)-pyrimidin-4-one
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidinones
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta