title: Synthesis, Activity, and Docking Study of Novel Phenylthiazole-Carboxamido Acid Derivatives as FFA2 Agonists.
abstract: Free fatty acid receptor 2 (FFA2), also known as GPR43, is activated by short-chain fatty acids (SCFAs) that are mainly produced by the gut microbiota through the fermentation of undigested carbohydrates and dietary fibers. FFA2 currently appears to be a potential target in the management of obesity, diabetes, inflammatory diseases, and cancer. In the study, a series of novel phenylthiazole-carboxamido acid derivatives has been synthesized and evaluated as potential orthosteric FFA2 ligands for the study of structure-activity relationships. Compound 6e was found to exhibit the twofold potent agonistic activity in the stable hFFA2-transfected CHO-K1 cells (EC50 = 23.1 μm) as that of positive control propionate (EC50 = 43.3 μm). We also reported the results of mutagenesis studies based on the crystal structure of hFFA1 bound to TAK-875 at 2.3 Å resolution to identify important residues for orthosteric agonist 6e inducing FFA2 activation.
authors.affiliation: Division of Nephrology, Kidney Research Institute, West China Hospital, West China Medical School of Sichuan University, Chengdu, 610041, China.|State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medical School of Sichuan University, Chengdu, 610041, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medical School of Sichuan University, Chengdu, 610041, China.
authors.forename: Taijin
authors.initials: T
authors.lastname: Wang
authors.affiliation: Division of Nephrology, Kidney Research Institute, West China Hospital, West China Medical School of Sichuan University, Chengdu, 610041, China.
authors.forename: Min
authors.initials: M
authors.lastname: Shi
authors.affiliation: Division of Nephrology, Kidney Research Institute, West China Hospital, West China Medical School of Sichuan University, Chengdu, 610041, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Fu
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medical School of Sichuan University, Chengdu, 610041, China.
authors.forename: Heying
authors.initials: H
authors.lastname: Pei
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medical School of Sichuan University, Chengdu, 610041, China.
authors.forename: Haoyu
authors.initials: H
authors.lastname: Ye
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D006801:Humans; D062105:Molecular Docking Simulation; D016296:Mutagenesis; D011956:Receptors, Cell Surface / Q000819:agonists / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled
chemical_list: D001572:Benzofurans; D011956:Receptors, Cell Surface; D013450:Sulfones; C473103:FFAR2 protein, human; D043562:Receptors, G-Protein-Coupled; C557331:TAK-875
keywords: FFA2; agonist activity; flexible docking; phenylthiazolecarboxamido acids