期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 50, 期 -, 页码 332-343出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2012.02.012
关键词
Enzyme inhibitor; Diabetes mellitus; Obesity; Protein tyrosine phosphatase; Insulinomimetic agent; Molecular docking
资金
- 'Ente Cassa di Risparmio di Firenze'
- University of Messina
In pursuing our research targeting the identification of potent inhibitors of PTP1B and LMW-PTP, we have identified new 4-[(5-arylidene-2-arylimino-4-oxo-3-thiazolidinyl)methyl]benzoic acids endowed with interesting in vitro inhibitory profiles. Most compounds proved to be inhibitors of PTP1B and LMW-PTP isoform IF1. The tested inhibitors also showed selectivity towards PTP1B over the closely related TC-PTP. These compounds were found to activate the insulin-mediated signalling on mouse C2C12 skeletal muscle cells by increasing the phosphorylation levels of the insulin receptor and promoting cellular 2-deoxyglucose uptake. Interestingly, 4-{[5-(4-benzyloxybenzylidene)-2-(4-trifluoromethylphenylmino)-4-oxo-3-thiazolidinyl]methyl}benzoic acid (7d), the best in vitro inhibitor of PTP1B and the isoform IF1 of LMW-PTP, provided the highest activation level of the insulin receptor and was found to be endowed with an excellent insulinomimetic effect on the selected cells. This compound therefore represents an interesting lead compound for developing novel PTP1B and LMW-PTP inhibitors which could be achieved by improving both its pharmacological profile and its potentiating effects on insulin signalling. (C) 2012 Elsevier Masson SAS. All rights reserved.
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