Synthesis and biological evaluation of picolinamides and thiazole-2-carboxamides as mGluR5 (metabotropic glutamate receptor 5) antagonists

Bioorg Med Chem Lett. 2016 Jan 1;26(1):140-4. doi: 10.1016/j.bmcl.2015.11.012. Epub 2015 Nov 5.

Abstract

We described here the synthesis and biological evaluation of picolinamides and thiazole-2-carboxamides as potential mGluR5 antagonists. We found that a series of thiazole derivatives 6 showed better inhibitory activity against mGluR5. Compounds 6bc and 6bj have been identified as potent antagonists (IC50=274 and 159nM) showing excellent in vitro stability profile. Molecular docking study using the crystal structure of mGluR5 revealed that our compounds 6bc and 6bj fit the allosteric binding site of mavoglurant well.

Keywords: Antagonist; Metabotropic glutamate receptor; Molecular docking; Picolinamides; Thiazole-2-carboxamides.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry
  • Amides / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Picolinic Acids / chemical synthesis*
  • Picolinic Acids / chemistry
  • Picolinic Acids / pharmacology*
  • Receptor, Metabotropic Glutamate 5 / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis
  • Thiazoles / chemistry
  • Thiazoles / pharmacology*

Substances

  • Amides
  • GRM5 protein, human
  • Picolinic Acids
  • Receptor, Metabotropic Glutamate 5
  • Thiazoles
  • picolinamide