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 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 IRß phosphorylation and 2-deoxyglucose cellular uptake.

[The new ERA-EDTA codes for primary kidney diseases]. / I nuovi codici ERA-EDTA delle malattie renali primitive.

The ERA-EDTA codes for primary renal disease (ERA-EDTA PRD code) were implemented many years ago as a tool to use during the annual census of the European Register. They encompassed all those kidney diseases that terminate in uremia, grouped together in various sections, to produce a document that, in a pre-computer age, would guarantee the simplicity of use required at the time, when the census was compiled manually. Over the years, the refinement of diagnostic techniques and the evolution of medical knowledge in general has limited the use of these codes. In addition, the expansion of computer technology has simplified word search in documents thereby permitting the use of far more complex lists containing greater numbers of codes. For this reason, ERA-EDTA has initiated a comprehensive revision of the PRD codes, producing a new list (ERA-EDTA PRD code 2012) which is considerably more detailed and thorough: for example, renal disease not leading to uremia is included, thereby extending the use of codes for scientific applications not restricted to dialysis. In addition, it is amenable to 'recoding' into different encoding systems, including ICD-10, SNOMED-CT data and the Mendelian Inheritance in Man. The new ERA-EDTA codes are accompanied by detailed notes to guide the user. Both codes and notes have been translated accurately into Italian and are now available on the site of the Italian Dialysis Register www.sin-ridt.org together with further information and a search tool for ease of use. This article introduces thenew codesand describesthe Italian language translation process.

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.