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 (PPAR alpha) 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 (PPAR delta, and PPAR gamma) have provided an opportunity to develop novel PPAR alpha-selective, PPAR alpha/gamma dual, and PPAR pan agonists. This review focuses on the molecular pharmacology of PPAR alpha, and summarizes our current design, synthesis, and evaluation of subtype-selective PPAR alpha agonists. The species selectivity of several classes of PPAR alpha selective agonists in response to in vitro PPAR alpha transactivation activity is also reported. These studies should help us to understand the structure-activity relationships and the mode of interaction between ligands and PPAR alpha, and also help to create novel therapeutic choices for the treatment of metabolic disorders.