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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.)

Diabetes mellitus (DM), a chronic metabolic disorder characterized by high blood glucose, not only poses a serious threat to human life and health, but also places an economic burden on society. Currently available antidiabetic pharmacological agents have some adverse effects, which have stimulated researchers to explore novel antidiabetic agents with different mechanisms of action. G-protein Coupled Receptor 120 (GPR120), also known as free fatty acid receptor 4 (FFAR4), which is activated by medium-chain and long-chain fatty acids, has emerged as an interesting potential target for the treatment of metabolic disorders. Herein, we designed and synthesized a series of novel GPR120 agonists based on the structure of TUG-891, which is susceptible to β -oxidation and loses its GPR120 agonistic activity in vivo. Among the designed compounds, 14d showed excellent agonistic activity and selectivity and could improve glucose tolerance in normal mice in a dose-dependent manner. In addition, the compound 14d displayed good antidiabetic effects in diet-induced obese (DIO) mice and elevated insulin levels. Molecular simulations illustrated that compound 14d could enter the active site of GPR120 and interact with ARG99, which plays an important role in GPR120 activation. Based on these observations, compound 14d may be a promising lead compound deserving of further biological evaluation and structural modifications.