Triazolopyridine ethers as potent, orally active mGlu 2 positive allosteric modulators for treating schizophrenia

Bioorg Med Chem. 2017 Jan 15;25(2):496-513. doi: 10.1016/j.bmc.2016.11.018. Epub 2016 Nov 14.

Abstract

Triazolopyridine ethers with mGlu2 positive allosteric modulator (PAM) activity are disclosed. The synthesis, in vitro activity, and metabolic stability data for a series of analogs is provided. The effort resulted in the discovery of a potent, selective, and brain penetrant lead molecule BMT-133218 ((+)-7m). After oral administration at 10mg/kg, BMT-133218 demonstrated full reversal of PCP-stimulated locomotor activity and prevented MK-801-induced working memory deficits in separate mouse models. Also, reversal of impairments in executive function were observed in rat set-shifting studies at 3 and 10mg/kg (p.o.). Extensive plasma protein binding as the result of high lipophilicity likely limited activity at lower doses. Optimized triazolopyridine ethers offer utility as mGlu2 PAMs for the treatment of schizophrenia and merit further preclinical investigation.

Keywords: Metabotropic glutamate receptors; Schizophrenia; Triazolopyridine; mGlu(2).

MeSH terms

  • Administration, Oral
  • Allosteric Regulation / drug effects
  • Animals
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Ethers / administration & dosage
  • Ethers / chemistry
  • Ethers / pharmacology*
  • Haplorhini
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular
  • Molecular Structure
  • Pyridines / administration & dosage
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors*
  • Receptors, Metabotropic Glutamate / metabolism
  • Schizophrenia / drug therapy*
  • Schizophrenia / metabolism
  • Structure-Activity Relationship
  • Triazoles / administration & dosage
  • Triazoles / chemistry
  • Triazoles / pharmacology*

Substances

  • Ethers
  • Pyridines
  • Receptors, Metabotropic Glutamate
  • Triazoles
  • metabotropic glutamate receptor 2