| Literature DB >> 27229618 |
Mikhail Krasavin1, Alexey Lukin2, Nikolay Zhurilo2, Alexey Kovalenko2, Ihor Zahanich3, Sergey Zozulya4, Daniel Moore5, Irina G Tikhonova5.
Abstract
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.Entities:
Keywords: Aqueous solubility; Bioisosteric replacement; FFA1 agonists; Free fatty acid receptor 1; GPR40; Metabolic stability; Total polar surface area; cLogP
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Year: 2016 PMID： 27229618 DOI： 10.1016/j.bmc.2016.04.065
Source DB: PubMed Journal: Bioorg Med Chem ISSN： 0968-0896 Impact factor: 3.641