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Bioorg Med Chem. 2016 Jul 1;24(13):2954-2963. doi: 10.1016/j.bmc.2016.04.065. Epub 2016 May 5.

Novel free fatty acid receptor 1 (GPR40) agonists based on 1,3,4-thiadiazole-2-carboxamide scaffold.

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Institutes of Chemistry and Translational Biomedicine, Saint Petersburg State University, Saint Petersburg 199034, Russian Federation. Electronic address:
Lomonosov Institute of Fine Chemical Technologies, Moscow Technological University, 86 Vernadskogo Prospekt, Moscow 117571, Russian Federation.
Enamine Ltd, 78 Chervonotkatska, Kyiv 02094, Ukraine.
Enamine Ltd, 78 Chervonotkatska, Kyiv 02094, Ukraine; Taras Shevchenko National University, 62 Volodymyrska, Kyiv 01033, Ukraine.
Molecular Therapeutics, School of Pharmacy, Medical Biology Centre, Queen's University Belfast, Belfast BT9 7BL, Northern Ireland, UK.


Free fatty acid receptor 1 (FFA1), previously known as GPR40 is a G protein-coupled receptor and a new target for treatment of type 2 diabetes. Two series of FFA1 agonists utilizing a 1,3,4-thiadiazole-2-caboxamide scaffold were synthetized. Both series offered significant improvement of the potency compared to the previously described 1,3,4-thiadiazole-based FFA1 agonists and high selectivity for FFA1. Molecular docking predicts new aromatic interactions with the receptor that improve agonist potency. The most potent compounds from both series were profiled for in vitro ADME properties (plasma and metabolic stability, LogD, plasma protein binding, hERG binding and CYP inhibition). One series suffered very rapid degradation in plasma and in presence of mouse liver microsomes. However, the other series delivered a lead compound that displayed a reasonable ADME profile together with the improved FFA1 potency.


Aqueous solubility; Bioisosteric replacement; FFA1 agonists; Free fatty acid receptor 1; GPR40; Metabolic stability; Total polar surface area; cLogP

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