Previous studies have revealed that PPARδ plays an important role in embryo implantation and that it has physiological functions in the differentiation of neuronal cells in the central nervous system (CNS) and in wound healing, exhibiting anti-inflammatory effects. Recent studies have also demonstrated that PPARδ is involved in lipid metabolism and muscle transformation. For example, PPARδ activates the expression of key genes involved in β-oxidation in fatty acid catabolism. PPARδ also affects uncoupling proteins (UCPs), which are involved in energy metabolism, and the effect of PPARδ on UCPs has positive effects on obesity. The activation of PPARδ increases HDL levels, improves type 2 diabetes without weight change, and favors the treatment of atherosclerosis by inhibiting the genes associated with atherosclerosis. Therefore, studies on the regulation of lipid metabolism using PPARδ have provided insight into the development of a treatment strategy for obesity and related metabolic diseases. In this poster, we synthesized novel PPARδ ligands by hybrid a known ligand and a marine natural product. An efficient synthetic route to these analogs was also developed. These compounds activated hPPARδ with EC50 values between 1 and 523 nM. Surprisingly, some of compounds were potent and selective hPPARδ agonists with 104-fold selectivity over the other two subtypes, namely, hPPARα and hPPARγ. Some selective PPARδ ligands showed good bioavailability and in vivo efficacy. These results suggest that our novel PPARδ agonists could be promising candidates for obesity and related metabolic diseases.

Discovery, design, and synthesis of peroxisome proliferator-activated receptor δ agonists

251st National Meeting (2016)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.