G蛋白偶联受体40激动剂TAK-875亚砜类似物的合成、绝对构型确证及生物活性研究(封面文章)
收稿日期: 2016-12-12
修回日期: 2017-02-16
网络出版日期: 2017-03-03
基金资助
国家自然科学基金（Nos.21302111，81373282）、山东省科技重大专项（No.2015ZDJS04001）、山东大学青年学者未来计划（No.2016WLJH33）资助项目.
Sulfoxide Analogs of TAK-875 as G Protein Coupled Receptor 40 Agonists: Synthesis, Determination of Absolute Configuration and Biological Activity
Received date: 2016-12-12
Revised date: 2017-02-16
Online published: 2017-03-03
Supported by
Project supported by the National Natural Science Foundation of China (Nos. 21302111, 81373282), the Major Project of Science and Technology of Shandong Province (No. 2015ZDJS04001), the Young Scholars Program of Shandong University (No. 2016WLJH33).
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 （EC50=84.3 nmol·L-1），11 （EC50=77.5 nmol·L-1），12 （EC50=76.1 nmol·L-1），13 （EC50=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.
闫玉刚 , 陈雪英 , 杨新颖 , 徐文方 , 张颖杰 . G蛋白偶联受体40激动剂TAK-875亚砜类似物的合成、绝对构型确证及生物活性研究(封面文章)[J]. 有机化学, 2017 , 37(4) : 858 -865 . DOI: 10.6023/cjoc201612041
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 optically 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 nmol·L-1) and its two optically pure epimers (12, EC50=76.1 nmol·L-1; 13, EC50=114.0 nmol·L-1) were comparable to that of compound 1 (EC50=84.3 nmol·L-1), which was rationalized by docking analysis. Compounds 12 and 13 warrant further drug-like property evaluation due to their promising potency and novel structures.
Key words： chirality; GPR40; sulfoxide; Circular dichroism
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