Molecular Characterization of Novel and Selective Peroxisome Proliferator-Activated Receptor α Agonists with Robust Hypolipidemic Activity in Vivo

The nuclear receptor peroxisome proliferator-activated receptor α (PPARα) is recognized as the primary target of the fibrate class of hypolipidemic drugs and mediates lipid lowering in part by activating a transcriptional cascade that induces genes involved in the catabolism of lipids. We report here the characterization of three novel PPARα agonists with therapeutic potential for treating dyslipidemia. These structurally related compounds display potent and selective binding to human PPARα and support robust recruitment of coactivator peptides in vitro. These compounds markedly potentiate chimeric transcription systems in cell-based assays and strikingly lower serum triglycerides in vivo. The transcription networks induced by these selective PPARα agonists were assessed by transcriptional profiling of mouse liver after short- and long-term treatment. The induction of several known PPARα target genes involved with fatty acid metabolism were observed, reflecting the expected pharmacology associated with PPARα activation. We also noted the down-regulation of a number of genes related to immune cell function, the acute phase response, and glucose metabolism, suggesting that these compounds may have anti-inflammatory action in the mammalian liver. Whereas these compounds are efficacious in acute preclinical models, extended safety studies and further clinical testing will be required before the full therapeutic promise of a selective PPARα agonist is realized.