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

作者：Krasavin Mikhail^*; Lukin Alexey; Zhurilo Nikolay; Kovalenko Alexey; Zahanich Ihor; Zozulya Sergey; Moore Daniel; Tikhonova Irina G

来源：Bioorganic & Medicinal Chemistry, 2016, 24(13): 2954-2963.

DOI：10.1016/j.bmc.2016.04.065

• GPR40
• Free fatty acid receptor 1
• FFA1 agonists
• Bioisosteric replacement
• Total polar surface area
• c Log P
• Metabolic stability
• Aqueous solubility

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, Log D, 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.

• 出版日期2016-7-1