Thieno[2,3-b]pyridines as negative allosteric modulators of metabotropic GluR5 receptors: Lead optimization

Bioorg Med Chem Lett. 2015 Apr 15;25(8):1724-1729. doi: 10.1016/j.bmcl.2015.02.073. Epub 2015 Mar 7.


An HTS campaign of our corporate compound library, and hit-to lead development resulted in thieno[2,3-b]pyridine derivative leads with mGluR5 negative allosteric modulator effects. During the lead optimization process, our objective was to improve affinity and metabolic stability. Modification of the first two targeted regions resulted in compounds with nanomolar affinity, then optimal substitution of the third region improved metabolic stability. One of the most promising compounds showed excellent in vivo efficacy and is a potential development candidate.

Keywords: Negative allosteric modulator; Thieno[2,3-b]pyridines; mGluR5.

MeSH terms

  • Allosteric Regulation
  • Animals
  • High-Throughput Screening Assays
  • Humans
  • Protein Binding
  • Pyrimidines / chemistry*
  • Pyrimidines / metabolism
  • Rats
  • Receptor, Metabotropic Glutamate 5 / chemistry*
  • Receptor, Metabotropic Glutamate 5 / metabolism
  • Structure-Activity Relationship


  • Pyrimidines
  • Receptor, Metabotropic Glutamate 5
  • thieno(2,3-d)pyrimidine