Citation: 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 shu

Sulfoxide Analogs of TAK-875 as G Protein Coupled Receptor 40 Agonists: Synthesis, Determination of Absolute Configuration and Biological Activity

Yan Yugang ^a ,
Chen Xueying ^b ,
Yang Xinying ^c ,
Xu Wenfang ^a,*,, ,
Zhang Yingjie ^a,*,,

a.
Institute of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan 250012
b.
Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Ji'nan 250012
c.
Institute of Pharmaceutical Analysis, School of Pharmacy, Shandong University, Ji'nan 250012

Corresponding author: Xu Wenfang, wenfxu@163.com Zhang Yingjie, zhangyingjie@sdu.edu.cn
Received Date: 12 December 2016
Revised Date: 16 February 2017

Fund Project: the National Natural Science Foundation of China 21302111the National Natural Science Foundation of China 81373282the Young Scholars Program of Shandong University 2016WLJH33the Major Project of Science and Technology of Shandong Province 2015ZDJS04001

Figures(5)

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.
- chirality,
- GPR40,
- sulfoxide,
- Circular dichroism
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