Peroxisome proliferator activated receptor gamma and oxidized docosahexaenoic acids as new class of ligand.

PPARgamma regulates the expression of numerous genes. In addition to their anti-diabetic activity, PPARgamma agonists have been reported to have beneficial effects for cancer, inflammation including inflammatory bowel disease, atherosclerosis and brain inflammation, as well as bone turnover. To investigate a potential new class of ligands for PPARgamma, we designed with reference to the crystal structure of the ligand-binding domain of PPARgamma oxidized docosahexaenoic acid (DHA) derivatives, which have a hydrophilic substituent at the C(4)-position and are putative metabolites of DHA. We synthesized 14 compounds and evaluated their activities in vitro. We found that these DHA derivatives show PPARgamma transactivation higher than, or comparable to, that of pioglitazone, which is a thiazolidinedione derivative used as an antidiabetic agent. Furthermore, one of them showed anti-diabetic activity in animal models. In this paper, we review the potential of PPARgamma as a drug target and oxidized DHA as a new class of ligand for PPARgamma.