Design, synthesis, and structure-activity relationship study of peroxisome proliferator-activated receptor (PPAR) δ-selective ligands

Improvements in our understanding of the functions of peroxisome proliferator-activated receptor (PPAR) subtypes as master regulators of many biological functions have made it possible to develop novel PPAR ligands with characteristic subtype selectivity as biochemical tools and/or candidatedrugs for the treatment of PPAR-dependent diseases such as metabolic syndrome, which includes type II diabetes, dyslipidemia, obesity, hypertension, and inflammation. Based on the findings that the glitazone-class antidiabetic agents, and fibrate-class antidyslipidemic agents are ligands of PPAR gamma and PPAR alpha respectively, much research interest has been focused on these two subtypes as therapeutic targets for the treatment of type II diabetes and dyslipidemia. In contrast, research interest in PPAR delta has been limited. However, since 2001, the availability of PPAR delta knockout animals and selective ligands has led to the uncovering of possible roles of PPAR delta in fatty acid metabolism, insulin resistance, reverse cholesterol transport, inflammation, and so on. It has become clear that ligands able to modulate PPAR delta-mediated pathways are candidates for the treatment of altered metabolic function. This review focuses on recent medicinal chemical studies to identify PPAR delta-selective agonists.