New 4-[(5-arylidene-2-arylimino-4-oxo-3-thiazolidinyl)methyl]benzoic acids active as protein tyrosine phosphatase inhibitors endowed with insulinomimetic effect on mouse C2C12 skeletal muscle cells

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-trifluoromethylphenylimino)-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.

Graphical abstractCompound 7d, the best inhibitor of PTP1B and the isoform IF1 of LMW-PTP, can promote the intracellular uptake of 2-DOG, therefore it can be considered an insulinomimetic agent.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► 5-Arylidene-2-arylimino-4-thiazolidinones inhibit PTP1B and LMW-PTP IF1 isoform. ► Compounds 7 proved to be endowed with excellent insulinomimetic effect. ► The best in vitro inhibitor 7d activates the IR to similar level to that of hormone. ► Compound 7d is endowed with an excellent insulinomimetic effect on the selected cells. ► Molecular modelling calculations allowed us to propose a hypothesis to explain SARs.