2. Academic Validation
  3. Identification of 1,3,4-Thiadiazolyl-Containing Thiazolidine-2,4-dione Derivatives as Novel PTP1B Inhibitors with Antidiabetic Activity

Identification of 1,3,4-Thiadiazolyl-Containing Thiazolidine-2,4-dione Derivatives as Novel PTP1B Inhibitors with Antidiabetic Activity

  • J Med Chem. 2024 May 23;67(10):8406-8419. doi: 10.1021/acs.jmedchem.4c00676.
Mengyue Li 1,  Huiyun Li 2 3,  Xiaofeng Min 1,  Jinping Sun 1,  Bingwen Liang 1,  Lei Xu 4,  Jia Li 4 3 5,  Shao-Hua Wang 6,  Xuetao Xu 1
Affiliations

Affiliations

  • 1 School of Pharmacy and Food Engineering & Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, Wuyi University, Jiangmen 529020, China.
  • 2 National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3 School of Pharmacy, Zunyi Medical University, Zunyi 563000, Guizhou, China.
  • 4 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, Guangdong, China.
  • 5 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 6 School of Pharmacy & State Key Laboratory of Applied Organic Chemistry & Collaborative Innovation Center for Northwestern Chinese Medicine, Lanzhou University, Lanzhou 730000, China.
PMID: 38723203 DOI: 10.1021/acs.jmedchem.4c00676
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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