title: 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 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.
authors.affiliation: Dipartimento Farmaco-chimico, University of Messina, Polo Universitario dell'Annunziata, Viale SS. Annunziata, 98168 Messina, Italy. rottana@unime.it
authors.forename: Rosaria
authors.initials: R
authors.lastname: Ottanà
authors.forename: Rosanna
authors.initials: R
authors.lastname: Maccari
authors.forename: Simona
authors.initials: S
authors.lastname: Amuso
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wolber
authors.forename: Daniela
authors.initials: D
authors.lastname: Schuster
authors.forename: Sonja
authors.initials: S
authors.lastname: Herdlinger
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Manao
authors.forename: Guido
authors.initials: G
authors.lastname: Camici
authors.forename: Paolo
authors.initials: P
authors.lastname: Paoli
mesh_terms: D000818:Animals; D001565:Benzoates / Q000138:chemical synthesis / Q000494:pharmacology*; D032701:Biomimetics; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D051379:Mice; D008956:Models, Chemical; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011487:Protein Conformation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors*; D011972:Receptor, Insulin / Q000378:metabolism; D053778:Thiazolidines / Q000138:chemical synthesis / Q000494:pharmacology*; D014443:Tyrosine / Q000378:metabolism
chemical_list: C573634:4-((5-(4-benzyloxybenzylidene)-2-(4-trifluoromethylphenylimino)-4-oxo-3-thiazolidinyl)methyl)benzoic acid; D001565:Benzoates; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D053778:Thiazolidines; D014443:Tyrosine; D011972:Receptor, Insulin; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1