3-(Pyridin-2-yl-ethynyl)benzamide metabotropic glutamate receptor 5 negative allosteric modulators: hit to lead studies

Bioorg Med Chem Lett. 2011 Jan 1;21(1):195-9. doi: 10.1016/j.bmcl.2010.11.038. Epub 2010 Nov 12.

Abstract

A series of 3-(pyridin-2-yl-ethynyl)benzamide negative allosteric modulators of the metabotropic glutamate receptor 5 (mGluR5 NAMs) have been prepared. Starting from HTS hit 1 (IC(50): 926 nM), potent mGluR5 NAMs showing excellent potencies (IC(50)s<50 nM) and good physicochemical profiles were prepared by monitoring LipE values. One compound 26 showed excellent mGluR5 binding (K(i): 21 nM) and antagonism (IC(50): 8 nM), an excellent rat PK profile (CL: 12 mL/min/kg, %F: 85) and showed oral activity in a mouse 4-Plate Behavioral model of anxiety (MED: 30 mpk) and a mouse Stress Induced Hyperthermia model of anxiety (MED 17.8 mpk).

MeSH terms

  • Allosteric Regulation
  • Animals
  • Anxiety Disorders / drug therapy
  • Benzamides / chemistry*
  • Benzamides / pharmacokinetics
  • Benzamides / therapeutic use
  • Disease Models, Animal
  • High-Throughput Screening Assays
  • Mice
  • Pyridines / chemistry*
  • Pyridines / pharmacokinetics
  • Pyridines / therapeutic use
  • Rats
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate / chemistry*
  • Receptors, Metabotropic Glutamate / metabolism

Substances

  • Benzamides
  • Grm5 protein, mouse
  • Grm5 protein, rat
  • Pyridines
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate
  • benzamide