期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 23, 期 22, 页码 7158-7164出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2015.10.011
关键词
FFA1 agonist; Phenoxyacetic acid; Ligand efficiency; Type 2 diabetes; Hypoglycemia
资金
- National Natural Science Foundation of China [81172932, 81273376]
- Natural Science Foundation of Jiangsu Province [BK2012356]
- Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University [JKGZ201103]
The free fatty acid receptor 1 (FFA1) is a novel antidiabetic target for the treatment of type 2 diabetes based on particular mechanism in amplifying glucose-stimulated insulin secretion. We have previously identified a series of phenoxyacetic acid derivatives. Herein, we describe the further chemical modification of this series directed by ligand efficiency and ligand lipophilicity efficiency. All of these efforts lead to the discovery of the promising candidate 16, an excellent FFA1 agonist with robust agonistic activity (43.6 nM), desired LE and LLE values. Moreover, compound 16 revealed a great potential for improving the hyperglycemia levels in both normal and type 2 diabetic mice without the risk of hypoglycemia even at the high dose of 40 mg/kg. (C) 2015 Elsevier Ltd. All rights reserved.
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