Discovery of VU0431316: a negative allosteric modulator of mGlu5 with activity in a mouse model of anxiety

Bioorg Med Chem Lett. 2014 Aug 1;24(15):3307-14. doi: 10.1016/j.bmcl.2014.06.003. Epub 2014 Jun 11.

Abstract

Development of SAR in an aryl ether series of mGlu5 NAMs leading to the identification of pyrazine analog VU0431316 is described in this Letter. VU0431316 is a potent and selective non-competitive antagonist of mGlu5 that binds at a known allosteric binding site. VU0431316 demonstrates an attractive DMPK profile, including moderate clearance and good bioavailability in rats. Intraperitoneal (IP) dosing of VU0431316 in a mouse marble burying model of anxiety, an assay known to be sensitive to mGlu5 antagonists and other anxiolytics, produced dose proportional effects.

Keywords: Allosteric modulator; Anxiety; CNS; Glutamate; mGlu(5).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Site / drug effects
  • Animals
  • Anxiety / drug therapy*
  • Disease Models, Animal*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Male
  • Mice
  • Molecular Structure
  • Picolinic Acids / administration & dosage
  • Picolinic Acids / chemistry
  • Picolinic Acids / pharmacology*
  • Pyrazines / administration & dosage
  • Pyrazines / chemistry
  • Pyrazines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Metabotropic Glutamate 5 / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Picolinic Acids
  • Pyrazines
  • Receptor, Metabotropic Glutamate 5
  • VU0431316