Synthesis, biological activity and structure–activity relationships of new benzoic acid-based protein tyrosine phosphatase inhibitors endowed with insulinomimetic effects in mouse C2C12 skeletal muscle cells

Insulin resistance is a complex altered metabolic condition characterized by impaired insulin signaling and implicated in the pathogenesis of serious human diseases, such as diabetes, obesity, neurodegenerative pathologies. In pursuing our aim to identify new agents able to improve cellular insulin...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2014-01, Vol.71, p.112-127
Main Authors: Ottanà, Rosaria, Maccari, Rosanna, Mortier, Jérémie, Caselli, Anna, Amuso, Simona, Camici, Guido, Rotondo, Archimede, Wolber, Gerhard, Paoli, Paolo
Format: Article
Language:English
Subjects:
4-[(5-Arylidene-4-oxo-2-phenylimino/oxothiazolidin-3-yl)methyl]benzoic acids
5-Arylidene-4-thiazolidinone derivatives
Animals
Benzoic Acid - chemical synthesis
Benzoic Acid - chemistry
Benzoic Acid - pharmacology
Cell Line
Enzyme inhibitors
Humans
Insulin - metabolism
Insulin Resistance
Insulinomimetic effects
Mice
Molecular docking
Molecular Docking Simulation
Muscle, Skeletal - cytology
Muscle, Skeletal - drug effects
Muscle, Skeletal - metabolism
Protein Tyrosine Phosphatase, Non-Receptor Type 1 - antagonists & inhibitors
Protein Tyrosine Phosphatase, Non-Receptor Type 1 - chemistry
Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism
Protein tyrosine phosphatases
Protein Tyrosine Phosphatases - antagonists & inhibitors
Protein Tyrosine Phosphatases - chemistry
Protein Tyrosine Phosphatases - metabolism
Structure-Activity Relationship
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Summary:Insulin resistance is a complex altered metabolic condition characterized by impaired insulin signaling and implicated in the pathogenesis of serious human diseases, such as diabetes, obesity, neurodegenerative pathologies. In pursuing our aim to identify new agents able to improve cellular insulin sensitivity, we have synthesized new 4-[(5-arylidene-4-oxo-2-phenylimino/oxothiazolidin-3-yl)methyl]benzoic acids (5, 8) and evaluated their inhibitory activity towards human protein tyrosine phosphatases PTP1B, LMW-PTP and TCPTP, enzymes which are involved in the development of insulin resistance. Compounds 5 and 8 showed from moderate to significant selectivity toward PTP1B over both the highly homologous TCPTP and the two isoforms of human LMW-PTP. In addition, most of the tested compounds selectively inhibited LMW-PTP IF1 over the isoform IF2. Docking studies into the active sites of PTP1B and LMW-PTP aided the rationalization of the observed PTP inhibitory profile. Moreover, most tested compounds were capable to induce the insulin metabolic pathway in mouse C2C12 skeletal muscle cells by remarkably stimulating both IRβ phosphorylation and 2-deoxyglucose cellular uptake. [Display omitted] •New benzoic acid-based protein tyrosine phosphatase inhibitors were identified.•They showed inhibitory activity toward human PTPs implicated in insulin resistance.•Docking studies aided the rationalization of the observed PTP inhibitory profile.•The new compounds were tested in cultures of mouse C2C12 skeletal muscle cells.•Most tested compounds exhibited good insulinomimetic effects in C2C12 cells.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2013.11.001