A Novel N-Substituted Valine Derivative with Unique Peroxisome Proliferator-Activated Receptor γbinding Properties and Biological Activities

Abstract

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(PPARI) activating properties. The systematic optimization of 3a, in order to improve its PPARγagonist activity, led to the synthesis of compound 7j (N-Aryl-substituted valine derivative) that possesses dual PPARI/PPARα agonistic activity. Structural and kinetic analyses reveal that 7j occupies the typical ligand binding domain of the PPARγagonists with, however, a unique high-Affinity binding mode. Furthermore, 7j is highly effective in preventing cyclin-dependent kinase 5-mediated phosphorylation of PPARγserine 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.