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

Abstract

A proprietary library of novel <i>N</i>-aryl-substituted amino acid derivatives bearing a hydroxamate head group allowed the identification of compound <b>3a</b> that possesses weak proadipogenic and peroxisome proliferator-activated receptor γ (PPARγ) activating properties. The systematic optimization of <b>3a</b>, in order to improve its PPARγ agonist activity, led to the synthesis of compound <b>7j</b> (<i>N</i>-aryl-substituted valine derivative) that possesses dual PPARγ/PPARα agonistic activity. Structural and kinetic analyses reveal that <b>7j</b> occupies the typical ligand binding domain of the PPARγ agonists with, however, a unique high-affinity binding mode. Furthermore, <b>7j</b> is highly effective in preventing cyclin-dependent kinase 5-mediated phosphorylation of PPARγ serine 273. Although less proadipogenic than rosiglitazone, <b>7j</b> significantly increases adipocyte insulin-stimulated glucose uptake and efficiently promotes white-to-brown adipocyte conversion. In addition, <b>7j</b> prevents oleic acid-induced lipid accumulation in hepatoma cells. The unique biochemical properties and biological activities of compound <b>7j</b> suggest that it would be a promising candidate for the development of compounds to reduce insulin resistance, obesity, and nonalcoholic fatty liver disease.