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An In Ovo Model for Testing Insulin-mimetic Compounds
Published on: April 23, 2018
Identification of 1,3,4-Thiadiazolyl-Containing Thiazolidine-2,4-dione Derivatives as Novel PTP1B Inhibitors with
Mengyue Li1, Huiyun Li2,3, Xiaofeng Min1
1School of Pharmacy and Food Engineering & Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, Wuyi University, Jiangmen 529020, China.
Abstract:
Forty-one 1,3,4-thiadiazolyl-containing thiazolidine-2,4-dione derivatives (MY1-41) were designed and synthesized as protein tyrosine phosphatase 1B (PTP1B) inhibitors with activity against diabetes mellitus (DM). All synthesized compounds (MY1-41) presented potential PTP1B inhibitory activities, with half-maximal inhibitory concentration (IC50) values ranging from 0.41 ± 0.05 to 4.68 ± 0.61 μM, compared with that of the positive control lithocholic acid (IC50 = 9.62 ± 0.14 μM). The most potent compound, MY17 (IC50 = 0.41 ± 0.05 μM), was a reversible, noncompetitive inhibitor of PTP1B. Circular dichroism spectroscopy and molecular docking were employed to analyze the binding interaction between MY17 and PTP1B. In HepG2 cells, MY17 treatment could alleviate palmitic acid (PA)-induced insulin resistance by upregulating the expression of phosphorylated insulin receptor substrate and protein kinase B. In vivo, oral administration of MY17 could reduce the fasting blood glucose level and improve glucose tolerance and dyslipidemia in mice suffering from DM.
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