1. Design, synthesis and biological evaluation of a series of novel GPR40 agonists containing nitrogen heterocyclic rings.
- Author
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Sun, Zhaozhu, Zhou, Tian, Pan, Xuan, Yang, Ying, Huan, Yi, Xiao, Zhiyan, Shen, Zhufang, and Liu, Zhanzhu
- Subjects
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DRUG synthesis , *DRUG design , *HETEROCYCLIC compounds , *CYCLIC compounds , *NITROGEN compounds , *PHENYL group - Abstract
A novel series of GPR40 agonists is designed by introducing nitrogen-containing heterocyclic ring at the terminal phenyl ring of TAK-875 with the aim of decreasing its lipophilicity. Three different β-substituted phenylpropionic acids were investigated as the acidic components. A total of 34 compounds have been synthesized, among which, compound 30 exhibited comparable GPR40 agonistic activity in vitro with TAK-875 and relatively lower lipophilicity through calculation ( 30 , EC 50 = 1.2 μM, cLogP = 1.3; TAK-875: EC 50 = 5.1 μM, cLogP = 3.4). Moreover, compound 30 was able to enhance the insulin secretion of primary islets isolated from normal ICR mice and showed no obvious inhibition against cytochromes P450 in vitro . In vivo , compound 30 exhibited efficacy in oral glucose tolerance test (oGTT) in normal ICR mice. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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