Chinese Journal of Organic Chemistry >
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 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
Yan Yugang , Chen Xueying , Yang Xinying , Xu Wenfang , Zhang Yingjie . Sulfoxide Analogs of TAK-875 as G Protein Coupled Receptor 40 Agonists: Synthesis, Determination of Absolute Configuration and Biological Activity[J]. Chinese Journal of Organic Chemistry, 2017 , 37(4) : 858 -865 . DOI: 10.6023/cjoc201612041
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