Discovery of 5-aryl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-ones as positive allosteric modulators of metabotropic glutamate subtype-2 (mGlu2) receptors with efficacy in a preclinical model of psychosis

Bioorg Med Chem Lett. 2016 Feb 15;26(4):1260-4. doi: 10.1016/j.bmcl.2016.01.021. Epub 2016 Jan 11.

Abstract

Optimization of a benzimidazolone template for potency and physical properties revealed 5-aryl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-ones as a key template on which to develop a new series of mGlu2 positive allosteric modulators (PAMs). Systematic investigation of aryl-SAR led to the identification of compound 27 as a potent and highly selective mGlu2 PAM with sufficient pharmacokinetics to advance to preclinical models of psychosis. Gratifyingly, compound 27 showed full efficacy in the PCP- and MK-801-induced hyperlocomotion assay in rats at CSF concentrations consistent with mGlu2 PAM potency.

Keywords: Metabotropic glutamate receptor; Positive allosteric modulator; Schizophrenia; mGlu2 PAM.

MeSH terms

  • Allosteric Regulation
  • Animals
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Imidazoles / blood
  • Imidazoles / chemistry*
  • Imidazoles / pharmacology
  • Imidazoles / therapeutic use
  • Locomotion / drug effects
  • Protein Binding
  • Psychotic Disorders / drug therapy
  • Psychotic Disorders / pathology
  • Pyridines / chemistry*
  • Pyridines / pharmacology
  • Pyridines / therapeutic use
  • Pyridones / blood
  • Pyridones / chemistry*
  • Pyridones / pharmacology
  • Rats
  • Receptors, Metabotropic Glutamate / chemistry*
  • Receptors, Metabotropic Glutamate / metabolism
  • Structure-Activity Relationship

Substances

  • Imidazoles
  • Pyridines
  • Pyridones
  • Receptors, Metabotropic Glutamate
  • imidazo(4,5-b)pyridine
  • metabotropic glutamate receptor 2