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

doi:10.6023/cjoc201612041

Chin. J. Org. Chem. ›› 2017, Vol. 37 ›› Issue (4): 858-865.DOI: 10.6023/cjoc201612041 Previous Articles Next Articles

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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)

闫玉刚^a, 陈雪英^b, 杨新颖^c, 徐文方^a, 张颖杰^a

a. 山东大学药学院药物化学研究所济南 250012;
b. 山东大学齐鲁医院教育部、卫生部心血管重构与功能研究重点实验室济南 250012;
c. 山东大学药学院药物分析研究所济南 250012

收稿日期:2016-12-12 修回日期:2017-02-16 发布日期:2017-03-03
通讯作者: 徐文方, 张颖杰 E-mail:wenfxu@163.com;zhangyingjie@sdu.edu.cn
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

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

Received:2016-12-12 Revised:2017-02-16 Published:2017-03-03
Contact: 10.6023/cjoc201612041 E-mail:wenfxu@163.com;zhangyingjie@sdu.edu.cn
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).

1. Sulfoxide Analogs of TAK-875 as G Protein Coupled Receptor 40 Agonists: Synthesis, Determination of Absolute Configuration and Biological Activity.PDF(2192KB)

Abstract

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

Cite this article

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]. Chin. J. Org. Chem., 2017, 37(4): 858-865.

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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)

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

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