中文摘要：

G蛋白偶联受体40（GPR40）是治疗二型糖尿病的潜在靶点.本研究首先合成TAK-875（1）作为检测GPR40激动活性的对照药物.进一步合成化合物1的亚砜类似物11.手性制备HPLC分离化合物11得到光学纯化合物12（S,S,100.0%de）和13（R,S,100.0%de）.其绝对构型通过圆二色谱确证.评价化合物1（EC_（50）=84.3 nmol·L（-1））,11（EC_（50）=77.5nmol·L（-1））,12（EC_（50）=76.1 nmol·L（-1））,13（EC_（50）=114.0 nmol·L（-1））对GPR40的激动活性,发现所合成的化合物体外保持了对照药物的活性.并通过计算机模拟对接的方法对活性保持的原因进行了解释.鉴于化合物12和13的良好活性与绝对构型的差别,下一步可分别对它们的成药性进行评价.

英文摘要：

G protein coupled receptor 40 （GPR40） is a potential target for treatment of type 2 diabetes. Herein, the well-known GPR40 agonist TAK-875 （compound 1） was synthesized as a positive control. Besides, an epimeric mixture 11, which was the sulfoxide analog of compound 1 was also synthesized. The following chiral HPLC separation of 11 led to opti- cally pure compounds 12 （S,S, 100.0% de） and 13 （R,S, 100.0% de）, of which the absolute configurations were determined by circular dichroism spectra analysis. In vitro biological activity evaluation results showed that the GPR40 agonistic potency of epimeric mixture 11 （EC50=77.5 nmoloL-I） and its two optically pure epimers （12, EC50=76.1 nmol.L-1; 13, ECs0----114.0 nmol-L-1） were comparable to that of compound 1 （EC50=84.3 nmol·L -l）, which was rationalized by docking analysis. Compounds 12 and 13 warrant further drug-like property evaluation due to their promising potency and novel structures.