2. Academic Validation
  3. Synthesis and biological evaluation of phenoxyacetic acid derivatives as novel free fatty acid receptor 1 agonists

Synthesis and biological evaluation of phenoxyacetic acid derivatives as novel free fatty acid receptor 1 agonists

  • Bioorg Med Chem. 2015 Jan 1;23(1):132-40. doi: 10.1016/j.bmc.2014.11.016.
Xuekun Wang 1,  Tianxiao Zhao 1,  Baowei Yang 2,  Zheng Li 1,  Jian Cui 1,  Yuxuan Dai 1,  Qianqian Qiu 1,  Hao Qiang 1,  Wenlong Huang 3,  Hai Qian 4
Affiliations

Affiliations

  • 1 Centre of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
  • 2 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.
  • 3 Centre of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address: ydhuangwenlong@126.com.
  • 4 Centre of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address: qianhai24@163.com.
PMID: 25481394 DOI: 10.1016/j.bmc.2014.11.016
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.

Keywords

FFA1 agonist; Oral glucose tolerance test; Phenoxyacetic acid; β-oxidation.

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