期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 16, 期 18, 页码 8697-8705出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2008.07.080
关键词
protein tyrosine phosphatase 1B; oleanolic acid; inhibitor; SAR (structure-activity relationship)
资金
- Chinese National Natural Science Foundation of China [30572241, 30623008]
- Shanghai Science and Technology Commission [04QMH1409]
Protein tyrosine phosphatase 1B is a key factor in the negative regulation of insulin pathway and a promising target for treatment of diabetes and obesity. Herein, a series of competitive inhibitors were optimized from oleanolic acid, a natural triterpenoid identified against PTP1B by screening libraries of traditional Chinese medicinal herbs. Modifying at 3 and 28 positions, we obtained compound 13 with a K-i of 130 nM, which exhibited good selectivity between other phosphatases involved in insulin pathway except T-cell protein tyrosine phosphatase. Further evaluation in cell models illustrated that the derivatives enhanced insulin receptor phosphorylation in CHO/hIR cells and also stimulated glucose uptake in L6 myotubes with or addition of without insulin. (C) 2008 Elsevier Ltd. All rights reserved.
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