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

• Published in: Journal of medicinal chemistry 2024-05, Vol.67 (10), p.8406-8419
• Main Authors: Li, Mengyue, Li, Huiyun, Min, Xiaofeng, Sun, Jinping, Liang, Bingwen, Xu, Lei, Li, Jia, Wang, Shao-Hua, Xu, Xuetao
• Format: Article
• Language: English
• Subjects: Animals; Blood Glucose - analysis; Blood Glucose - drug effects; Blood Glucose - metabolism; Diabetes Mellitus, Experimental - drug therapy; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Hep G2 Cells; Humans; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - therapeutic use; Insulin Resistance; Male; Mice; Molecular Docking Simulation; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - antagonists & inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism; Structure-Activity Relationship; Thiadiazoles - chemical synthesis; Thiadiazoles - chemistry; Thiadiazoles - pharmacology; Thiazolidinediones - chemical synthesis; Thiazolidinediones - chemistry; Thiazolidinediones - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.4c00676

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.