Fragment and Structure-Based Drug Discovery for a Class C GPCR: Discovery of the mGlu5 Negative Allosteric Modulator HTL14242 (3-Chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile)

J Med Chem. 2015 Aug 27;58(16):6653-64. doi: 10.1021/acs.jmedchem.5b00892. Epub 2015 Aug 12.

Abstract

Fragment screening of a thermostabilized mGlu5 receptor using a high-concentration radioligand binding assay enabled the identification of moderate affinity, high ligand efficiency (LE) pyrimidine hit 5. Subsequent optimization using structure-based drug discovery methods led to the selection of 25, HTL14242, as an advanced lead compound for further development. Structures of the stabilized mGlu5 receptor complexed with 25 and another molecule in the series, 14, were determined at resolutions of 2.6 and 3.1 Å, respectively.

MeSH terms

  • Allosteric Regulation
  • Animals
  • Caco-2 Cells
  • Dogs
  • Drug Design
  • Drug Discovery
  • HEK293 Cells
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Conformation
  • Pyridines / chemical synthesis*
  • Pyridines / pharmacokinetics
  • Pyridines / pharmacology*
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / pharmacology*
  • Rats
  • Receptor, Metabotropic Glutamate 5 / drug effects*
  • Receptors, G-Protein-Coupled / drug effects*
  • Structure-Activity Relationship

Substances

  • 3-chloro-5-(6-(5-fluoropyridin-2-yl)pyrimidin-4-yl)benzonitrile
  • Grm5 protein, rat
  • Ligands
  • Pyridines
  • Pyrimidines
  • Receptor, Metabotropic Glutamate 5
  • Receptors, G-Protein-Coupled

Associated data

  • PDB/5CGC
  • PDB/5CGD