title: Synthesis and biological evaluation of phenoxyacetic acid derivatives as novel free fatty acid receptor 1 agonists.
abstract: Free fatty acid receptor 1 (FFA1) is a new potential drug target for the treatment of type 2 diabetes because of its role in amplifying glucose-stimulated insulin secretion in pancreatic β-cell. In the present studies, we identified phenoxyacetic acid derivative (18b) as a potent FFA1 agonist (EC50=62.3 nM) based on the structure of phenylpropanoic acid derivative 4p. Moreover, compound 18b could significantly improve oral glucose tolerance in ICR mice and dose-dependently reduced glucose levels in type 2 diabetic C57BL/6 mice without observation of hypoglycemic side effect. Additionally, compound 18b exhibited acceptable PK profiles. In summary, compound 18b with ideal PK profiles exhibited good activity in vitro and in vivo, and might be a promising drug candidate for the treatment of diabetes mellitus.
authors.affiliation: Centre of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Xuekun
authors.initials: X
authors.lastname: Wang
authors.affiliation: Centre of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Tianxiao
authors.initials: T
authors.lastname: Zhao
authors.affiliation: Centre of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China; Medical and Health Management Department, Jiangsu Food & Pharmaceutical Science College, 4 Meicheng South Road, Higher Education Area, Huaian, Jiangsu 223003, China.
authors.forename: Baowei
authors.initials: B
authors.lastname: Yang
authors.affiliation: Centre of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
authors.affiliation: Centre of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Cui
authors.affiliation: Centre of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Yuxuan
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Centre of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Qiu
authors.affiliation: Centre of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Qiang
authors.affiliation: Centre of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address: ydhuangwenlong@126.com.
authors.forename: Wenlong
authors.initials: W
authors.lastname: Huang
authors.affiliation: Centre of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address: qianhai24@163.com.
authors.forename: Hai
authors.initials: H
authors.lastname: Qian
mesh_terms: D000085:Acetates / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008958:Models, Molecular; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000085:Acetates; C473034:FFAR1 protein, human; D043562:Receptors, G-Protein-Coupled; C415326:phenoxyacetic acid
keywords: FFA1 agonist; Oral glucose tolerance test; Phenoxyacetic acid; β-oxidation