Diphenyl Ether Derivatives as Novel GPR120 Agonists for the Treatment of Type 2 Diabetes Mellitus.

Autor: Wang X; School of Pharmaceutical Sciences, Liaocheng University, 1 Hunan Street, Liaocheng, Shandong 252059, China., Wei S; School of Pharmaceutical Sciences, Liaocheng University, 1 Hunan Street, Liaocheng, Shandong 252059, China., Wang M; School of Pharmaceutical Sciences, Liaocheng University, 1 Hunan Street, Liaocheng, Shandong 252059, China., Xu Y; School of Pharmaceutical Sciences, Liaocheng University, 1 Hunan Street, Liaocheng, Shandong 252059, China., Hu W; School of Pharmaceutical Sciences, Liaocheng University, 1 Hunan Street, Liaocheng, Shandong 252059, China., Niu M; School of Pharmaceutical Sciences, Liaocheng University, 1 Hunan Street, Liaocheng, Shandong 252059, China., Wang S; School of Pharmaceutical Sciences, Liaocheng University, 1 Hunan Street, Liaocheng, Shandong 252059, China., Lei K; School of Pharmaceutical Sciences, Liaocheng University, 1 Hunan Street, Liaocheng, Shandong 252059, China., Ji L; School of Pharmaceutical Sciences, Liaocheng University, 1 Hunan Street, Liaocheng, Shandong 252059, China., Liu R; School of Pharmaceutical Sciences, Liaocheng University, 1 Hunan Street, Liaocheng, Shandong 252059, China., Ji G; School of Pharmaceutical Sciences, Liaocheng University, 1 Hunan Street, Liaocheng, Shandong 252059, China.; School of Chemistry and Chemical Engineering, Liaocheng University, 1 Hunan Street, Liaocheng, Shandong 252059, China.
Jazyk: angličtina
Zdroj: Chemistry & biodiversity [Chem Biodivers] 2023 Jan; Vol. 20 (1), pp. e202200814. Date of Electronic Publication: 2022 Dec 16.
DOI: 10.1002/cbdv.202200814
Abstrakt: Diabetes mellitus (DM) is a serious disease affecting human health. Numerous attempts have been made to develop safe and effective new antidiabetic drugs. Recently, a series of G protein-coupled receptors for free fatty acids (FFAs) have been described and characterized, and small molecule agonists and antagonists of these receptors show considerable promise for managing diabetes and related complications. FFA-activated GPR120 could stimulate the release of glucagon-like peptide-1(GLP-1), which can enhance the glucose-dependent secretion of insulin from pancreatic β cells. GPR120 is a promising target for treating type 2 DM (T2DM). Herein we designed and synthesized a series of novel GPR120 agonists based on the structure of TUG-891, which was the first potent and selective GPR120 agonist. Among the designed compounds, 18 f showed excellent GPR120 activation activity and high selectivity for GPR40 in vitro. Compound 18 f dose-dependently improved glucose tolerance in normal mice, and no hypoglycemic side effects were observed at high dose. In addition, compound 18 f increased insulin release and displayed good antidiabetic effect in diet-induced obese mice. Molecular simulations illustrated that compound 18 f could enter the active site of GPR120 and interact with Arg99. Based on these observations, compound 18 f may be a promising lead compound for the design of novel GPR120 agonists to treat T2DM.
(© 2022 Wiley-VHCA AG, Zurich, Switzerland.)
Databáze: MEDLINE
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