Résumé
A proprietary library of novel N-aryl substituted amino acid derivatives bearing hydroxamate head group allowed the identification of compound 3a that possesses weak proadipogenic and PPAR activating properties. The systematic optimization of 3a, in order to improve its PPAR agonist activity, led to the synthesis of compound 7j (N-aryl substituted valine derivative) that possesses dual PPAR / PPAR agonistic activity. Structural and kinetic analyses reveal that 7j occupies the typical ligand binding domain of the PPAR agonists with, however, a unique high-affinity binding mode. Furthermore, 7j is highly effective in preventing CDK5-mediated phosphorylation of PPAR serine 273. Although less proadipogenic than rosiglitazone, 7j significantly increases adipocyte insulin-stimulated glucose uptake and efficiently promotes white-to-brown adipocyte conversion. In addition, 7j prevents the palmitate-induced lipid accumulation in hepatoma cells. The unique biochemical properties and biological activities of compound 7j suggest its potential efficacy in reducing insulin resistance, obesity and non-alcoholic fatty liver disease.