Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CHO Cells
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Cell Line / drug effects
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Cell Line / metabolism
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Cricetinae
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Cricetulus
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Diabetes Mellitus / metabolism
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Diabetes Mellitus / pathology
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Drugs, Chinese Herbal / chemical synthesis
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Drugs, Chinese Herbal / pharmacology*
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / pharmacology*
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Humans
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Insulin / metabolism*
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Obesity / metabolism
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Obesity / pathology
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Oleanolic Acid / analogs & derivatives
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Oleanolic Acid / chemical synthesis
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Oleanolic Acid / pharmacology*
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Phosphorylation
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Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
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Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
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Receptor, Insulin / drug effects
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Receptor, Insulin / metabolism
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Structure-Activity Relationship
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T-Lymphocytes / enzymology
Substances
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Drugs, Chinese Herbal
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Enzyme Inhibitors
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Insulin
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Oleanolic Acid
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Receptor, Insulin
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Protein Tyrosine Phosphatase, Non-Receptor Type 1