Discovery of novel 2-(alkylmorpholin-4-yl)-6-(3-fluoropyridin-4-yl)-pyrimidin-4(3H)-ones as orally-active GSK-3β inhibitors for Alzheimer's disease

Bioorg Med Chem Lett. 2015 Mar 1;25(5):1086-91. doi: 10.1016/j.bmcl.2015.01.005. Epub 2015 Jan 13.

Abstract

We herein describe the results of further evolution of GSK-3β inhibitors for Alzheimer's disease from our promising compounds with in vivo tau phosphorylation inhibitory activity by oral administration. Introduction of a low alkyl group instead of the phenyl group at the 3-position of the morpholine moiety aiming to improve pharmacokinetic profiles resulted in potent low molecular weight GSK-3β inhibitors with good in vitro pharmacokinetic profiles, which also showed in vivo tau phosphorylation inhibitory activity by oral administration. Effect of the stereochemistry of the alkyl moiety is also discussed using docking models.

Keywords: Alkylmorpholine; Alzheimer’s disease; Glycogen synthase kinase 3β.

MeSH terms

  • Administration, Oral
  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / enzymology*
  • Alzheimer Disease / metabolism
  • Animals
  • Drug Discovery
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Mice
  • Molecular Docking Simulation
  • Morpholines / administration & dosage
  • Morpholines / chemistry*
  • Morpholines / pharmacokinetics
  • Morpholines / pharmacology*
  • Phosphorylation / drug effects
  • Pyrimidines / administration & dosage
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / pharmacology*
  • tau Proteins / metabolism

Substances

  • Morpholines
  • Pyrimidines
  • tau Proteins
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Glycogen Synthase Kinase 3