| Autor: |
Peiretti F; Aix Marseille University, INSERM, INRAE, C2VN, 13385 Marseille, France., Montanari R; Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Via Salaria km. 29.300, Monterotondo Stazione, 00015 Rome, Italy., Capelli D; Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Via Salaria km. 29.300, Monterotondo Stazione, 00015 Rome, Italy., Bonardo B; Aix Marseille University, INSERM, INRAE, C2VN, 13385 Marseille, France., Colson C; Université Côte d'Azur, CNRS, Inserm, iBV, 06108 Nice, France., Amri EZ; Université Côte d'Azur, CNRS, Inserm, iBV, 06108 Nice, France., Grimaldi M; Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM, University of Montpellier, ICM, 34298 Montpellier, France., Balaguer P; Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM, University of Montpellier, ICM, 34298 Montpellier, France., Ito K; Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, New York 10065, United States., Roeder RG; Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, New York 10065, United States., Pochetti G; Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Via Salaria km. 29.300, Monterotondo Stazione, 00015 Rome, Italy., Brunel JM; Aix Marseille University, INSERM, SSA, MCT, 13385 Marseille, France. |
| Abstrakt: |
A proprietary library of novel N -aryl-substituted amino acid derivatives bearing a hydroxamate head group allowed the identification of compound 3a that possesses weak proadipogenic and peroxisome proliferator-activated receptor γ (PPARγ) activating properties. The systematic optimization of 3a , in order to improve its PPARγ agonist activity, led to the synthesis of compound 7j ( N -aryl-substituted valine derivative) that possesses dual PPARγ/PPARα agonistic activity. Structural and kinetic analyses reveal that 7j occupies the typical ligand binding domain of the PPARγ agonists with, however, a unique high-affinity binding mode. Furthermore, 7j is highly effective in preventing cyclin-dependent kinase 5-mediated phosphorylation of PPARγ 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 oleic acid-induced lipid accumulation in hepatoma cells. The unique biochemical properties and biological activities of compound 7j suggest that it would be a promising candidate for the development of compounds to reduce insulin resistance, obesity, and nonalcoholic fatty liver disease. |
