3-Cyano-5-fluoro-N-arylbenzamides as negative allosteric modulators of mGlu(5): Identification of easily prepared tool compounds with CNS exposure in rats

Bioorg Med Chem Lett. 2010 Aug 1;20(15):4390-4. doi: 10.1016/j.bmcl.2010.06.064. Epub 2010 Jun 15.

Abstract

Development of SAR in a 3-cyano-5-fluoro-N-arylbenzamide series of non-competitive antagonists of mGlu(5) using a functional cell-based assay is described in this Letter. Further characterization of selected potent compounds in in vitro assays designed to measure their metabolic stability and protein binding is also presented. Subsequent evaluation of two new compounds in pharmacokinetic studies using intraperitoneal dosing in rats demonstrated good exposure in both plasma and brain samples.

Publication types

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

MeSH terms

  • Allosteric Regulation
  • Animals
  • Benzamides / chemical synthesis
  • Benzamides / chemistry*
  • Benzamides / pharmacokinetics
  • Blood Proteins / metabolism
  • Brain / metabolism
  • Microsomes, Liver / metabolism
  • Protein Binding
  • Rats
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors*
  • Receptors, Metabotropic Glutamate / chemistry
  • Receptors, Metabotropic Glutamate / metabolism
  • Structure-Activity Relationship

Substances

  • Benzamides
  • Blood Proteins
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate