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

ABSTRACT: 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 isoformIF1 of LMW-PTP, provided the highest activation level of the insulin receptor and was found to be endowed with an excellent insulino-mimetic 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.