Discovery of new acylaminopyridines as GSK-3 inhibitors by a structure guided in-depth exploration of chemical space around a pyrrolopyridinone core

Bioorg Med Chem Lett. 2015 May 1;25(9):1856-63. doi: 10.1016/j.bmcl.2015.03.046. Epub 2015 Mar 24.

Abstract

Glycogen synthase kinase-3 (GSK-3) has been proposed to play a crucial role in the pathogenesis of many diseases including cancer, stroke, bipolar disorders, diabetes and neurodegenerative diseases. GSK-3 inhibition has been a major area of pharmaceutical interest over the last two decades. A plethora of reports appeared recently on selective inhibitors and their co-crystal structures in GSK-3β. We identified several series of promising new GSK-3β inhibitors from a coherent design around a pyrrolopyridinone core structure. A systematic exploration of the chemical space around the central spacer led to potent single digit and sub-nanomolar GSK-3β inhibitors. When dosed orally in a transgenic mouse model of Alzheimer's disease (AD), an exemplary compound showed significant lowering of Tau phosphorylation at one of the GSK-3 phosphorylating sites, Ser396. X-ray crystallography greatly aided in validating the binding hypotheses.

Keywords: Alzheimer’s disease; GSK-3; Kinase; Pyrrolopyridinone; Tau-phosphorylation.

MeSH terms

  • Aminopyridines / administration & dosage
  • Aminopyridines / chemistry
  • Aminopyridines / pharmacology*
  • Animals
  • Crystallography, X-Ray
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 / metabolism
  • Humans
  • Mice
  • Mice, Transgenic
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyridones / chemistry*
  • Pyrroles / chemistry*
  • Structure-Activity Relationship

Substances

  • Aminopyridines
  • Protein Kinase Inhibitors
  • Pyridones
  • Pyrroles
  • Glycogen Synthase Kinase 3