Synthesis and SAR of a mGluR5 allosteric partial antagonist lead: unexpected modulation of pharmacology with slight structural modifications to a 5-(phenylethynyl)pyrimidine scaffold

Bioorg Med Chem Lett. 2008 Jul 15;18(14):4098-101. doi: 10.1016/j.bmcl.2008.05.091. Epub 2008 May 29.

Abstract

This Letter describes the synthesis and SAR, developed through an iterative analogue library approach, of a mGluR5 allosteric partial antagonist lead based on a 5-(phenylethynyl)pyrimidine scaffold. With slight structural modifications to the distal phenyl ring, analogues demonstrated a range of pharmacological activities from mGluR5 partial antagonism to full antagonism/negative allosteric modulation to positive allosteric modulation.

Publication types

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

MeSH terms

  • Allosteric Regulation / drug effects
  • Allosteric Site
  • Animals
  • Binding, Competitive
  • Chemistry, Pharmaceutical / methods
  • Drug Design
  • Humans
  • Inhibitory Concentration 50
  • Ligands
  • Models, Chemical
  • Pyrimidines / chemistry
  • Rats
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors*
  • Receptors, Metabotropic Glutamate / chemistry
  • Structure-Activity Relationship
  • Time Factors

Substances

  • GRM5 protein, human
  • Grm5 protein, rat
  • Ligands
  • Pyrimidines
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate