Discovery of dihydropyrazino-benzimidazole derivatives as metabotropic glutamate receptor-2 (mGluR2) positive allosteric modulators (PAMs)

Eur J Med Chem. 2020 Jan 15:186:111881. doi: 10.1016/j.ejmech.2019.111881. Epub 2019 Nov 15.

Abstract

A scaffold hopping strategy converted the known 1-[(1-methyl-1H-imidazol-2-yl)methyl]-4-phenylpiperidine core (1 and 2) by cyclization to a fused [6 + 5+6] membered heterocyclic mGluR2 PAM scaffold. Pharmacophore guided structure-activity relationship (SAR) studies resulted in a series of potent and metabolically stable mGluR2 PAMs. A representative optimized compound (95) having the most balanced profile, demonstrated efficacy in the PCP-induced hyper-locomotion model in mice that revealed the new chemotype being a promising PAM lead targeting mGluR2 receptors and providing support for further translational studies.

Keywords: Dihydropyrazino-benzimidazoles; Pharmacophore based optimization; Positive allosteric modulator; Scaffold hopping; mGlu(2) receptor.

MeSH terms

  • Allosteric Regulation / drug effects
  • Animals
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology*
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Mice
  • Microsomes, Liver / chemistry
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Pyrazines / chemistry
  • Pyrazines / pharmacology*
  • Rats
  • Rats, Wistar
  • Receptors, Metabotropic Glutamate / metabolism*
  • Structure-Activity Relationship

Substances

  • Benzimidazoles
  • Pyrazines
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor 2
  • benzimidazole