期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 23, 期 1, 页码 132-140出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2014.11.016
关键词
FFA1 agonist; Phenoxyacetic acid; beta-oxidation; Oral glucose tolerance test
资金
- National Natural Science Foundation of China [81172932, 81273376]
- Natural Science Foundation of Jiangsu Province [BK2012356]
- State Key Laboratory of Natural Medicines, China Pharmaceutical University [JKGZ201103]
Free fatty acid receptor 1 (FFA1) is a new potential drug target for the treatment of type 2 diabetes because of its role in amplifying glucose-stimulated insulin secretion in pancreatic beta-cell. In the present studies, we identified phenoxyacetic acid derivative (18b) as a potent FFA1 agonist (EC50 = 62.3 nM) based on the structure of phenylpropanoic acid derivative 4p. Moreover, compound 18b could significantly improve oral glucose tolerance in ICR mice and dose-dependently reduced glucose levels in type 2 diabetic C57BL/6 mice without observation of hypoglycemic side effect. Additionally, compound 18b exhibited acceptable PK profiles. In summary, compound 18b with ideal PK profiles exhibited good activity in vitro and in vivo, and might be a promising drug candidate for the treatment of diabetes mellitus. (C) 2014 Elsevier Ltd. All rights reserved.
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