期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 24, 期 21, 页码 5449-5454出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2016.08.068
关键词
FFA1 agonist; GPR40; Triazole core; Click chemistry; Type 2 diabetes
资金
- National Natural Science Foundation of China [81172932, 81273376]
- Natural Science Foundation of Jiangsu Province [BK2012356]
- innovation project of Jiangsu Province [KYLX16_1175]
- Fundamental Research Funds for the Central Universities, China Pharmaceutical University [JKZD2013001]
The free fatty acid receptor 1 (FFA1/GPR40) is a novel antidiabetic target based on particular mechanism in enhancing glucose-stimulated insulin secretion. Most of reported FFA1 agonists, however, have been suffered from relatively high lipophilicity and molecular weight. Aiming to develop potent agonists with improved physicochemical property, 25 compounds containing triazole scaffold and various carboxylic acid fragments were synthesized via the click chemistry. Among them, the optimal lead compound 26 with relatively low lipophicity (LogD(7.4) = 1.95) and molecular weight (Mw = 391.78) exhibited a considerable FFA1 agonistic activity (36.15%). In addition, compound 26 revealed a significant improvement in the glucose tolerance with a 21.4% and 14.2% reduction of glucose AUC(0-2h) in normal ICR mice and type 2 diabetic C57BL/6 mice, respectively. All of these results demonstrated that compound 26 was considered to be a promising lead compound suitable for further optimization. (C) 2016 Elsevier Ltd. All rights reserved.
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