Synthesis and SAR of novel, non-MPEP chemotype mGluR5 NAMs identified by functional HTS

Bioorg Med Chem Lett. 2009 Dec 1;19(23):6502-6. doi: 10.1016/j.bmcl.2009.10.059. Epub 2009 Oct 28.

Abstract

This Letter describes the discovery and SAR of three novel series of mGluR5 non-competitive antagonists/negative allosteric modulators (NAMs) not based on manipulation of an MPEP/MTEP chemotype identified by a functional HTS approach. This work demonstrates fundamentally new mGluR5 NAM chemotypes with submicromolar potencies, and further examples of a mode of pharmacology 'switch' to provide PAMs with a non-MPEP scaffold.

Publication types

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

MeSH terms

  • Benzamides / chemical synthesis*
  • Benzamides / chemistry
  • Benzamides / pharmacology*
  • Benzimidazoles / chemical synthesis*
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology*
  • High-Throughput Screening Assays / methods*
  • Molecular Structure
  • Phthalimides / chemical synthesis*
  • Phthalimides / chemistry
  • Phthalimides / pharmacology*
  • Pyridines / chemistry
  • Pyridines / pharmacology
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Thiazoles / chemistry
  • Thiazoles / pharmacology

Substances

  • 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine
  • 3-(phthalimidyl)-N-(2-hydroxyphenyl)benzamide
  • Benzamides
  • Benzimidazoles
  • N-(3-(1H-benzo(d)imidazol-2-yl)-4-chlorophenyl)-5-bromofuran-2-carboxamide
  • Phthalimides
  • Pyridines
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate
  • Thiazoles
  • 6-methyl-2-(phenylethynyl)pyridine