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
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新型游离脂肪酸受体1激动剂苯氧乙酸衍生物的合成及生物学评价
DOI：
10.1016/j.bmc.2014.11.016
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发表时间：
2015-01-01
影响因子：
3.5
通讯作者：
Qian, Hai
中科院分区：
文献类型：
--
作者：
Wang, Xuekun;Zhao, Tianxiao;Qian, Hai
游离脂肪酸受体1（Free Fatty Acid Receptor 1，FFA 1）是治疗2型糖尿病的一个潜在药物靶点，它能增强葡萄糖刺激的胰岛β细胞胰岛素分泌。在本研究中，我们基于苯丙酸衍生物4p的结构鉴定了苯氧基乙酸衍生物（18 b）作为有效的FFA 1激动剂（EC 50 = 62.3 nM）。此外，化合物18 b可以显著改善ICR小鼠的口服葡萄糖耐量，并剂量依赖性地降低2型糖尿病C57 BL/6小鼠的葡萄糖水平，而没有观察到低血糖副作用。此外，化合物18 b表现出可接受的PK特征。综上所述，化合物18 b具有理想的药代动力学特征，在体内外均表现出良好的活性，有望成为治疗糖尿病的候选药物。(C)2014爱思唯尔有限公司版权所有。
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 beta-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. (C) 2014 Elsevier Ltd. All rights reserved.