Design and synthesis of subtype- and species-selective peroxisome proliferator-activated receptor (PPAR) alpha ligands

The molecular pharmacological discovery of the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha) as the master regulator of lipid and lipoprotein homeostasis, and the rapid development of a parallel screening approach to evaluate activity towards other PPAR subtypes (PPARdelta, and PPARgamma) have provided an opportunity to develop novel PPAR alpha-selective, PPARalpha/gamma dual, and PPAR pan agonists. This review focuses on the molecular pharmacology of PPARalpha, and summarizes our current design, synthesis, and evaluation of subtype-selective PPARalpha agonists. The species selectivity of several classes of PPARalpha selective agonists in response to in vitro PPARalpha transactivation activity is also reported. These studies should help us to understand the structure-activity relationships and the mode of interaction between ligands and PPARalpha, and also help to create novel therapeutic choices for the treatment of metabolic disorders.