Continued SAR exploration of 1,2,4-thiadiazole-containing scaffolds in the design of free fatty acid receptor 1 (GPR40) agonists

Eur J Med Chem. 2017 Nov 10;140:229-238. doi: 10.1016/j.ejmech.2017.09.019. Epub 2017 Sep 13.


An earlier reported series of 1,2,4-thiadiazole-based agonists of FFA1 (GPR40) was evolved into two structurally distinct series of compounds. One of the series (structurally related to known FFA1 agonist GW9508) displayed low micromolar potency while the other (representing a truncated version of the earlier reported potent FFA1 agonists) was, surprisingly, found to be devoid of agonist potency. In silico docking of representative compounds into the crystal structure of FFA1 revealed possible structural grounds for the observed SAR.

Keywords: 1,2,4-Thiadiazole; Agonist potency; Free fatty acid receptor 1; GPR40; Heterocyclic bioisosteres; In silico docking.

MeSH terms

  • Animals
  • CHO Cells
  • Cricetulus
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Receptors, G-Protein-Coupled / agonists*
  • Structure-Activity Relationship
  • Thiadiazoles / chemical synthesis
  • Thiadiazoles / chemistry
  • Thiadiazoles / pharmacology*


  • FFAR1 protein, human
  • Receptors, G-Protein-Coupled
  • Thiadiazoles