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

Mengyue Li; Huiyun Li; Xiaofeng Min; Jinping Sun; Bingwen Liang; Lei Xu; Jia Li; Shao-Hua Wang; Xuetao Xu

doi:10.1021/acs.jmedchem.4c00676

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. Epub 2024 May 9.

Authors

Mengyue Li¹, Huiyun Li^{2

3}, Xiaofeng Min¹, Jinping Sun¹, Bingwen Liang¹, Lei Xu⁴, Jia Li^{4

3

5}, Shao-Hua Wang⁶, Xuetao Xu¹

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.

MeSH terms

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

Substances

Protein Tyrosine Phosphatase, Non-Receptor Type 1
Hypoglycemic Agents
Thiazolidinediones
thiazolidine-2,4-dione
Thiadiazoles
PTPN1 protein, human
Enzyme Inhibitors
Blood Glucose