Chem. Pharm. Bull. 55(7) 1053—1059 (2007)

PPARg and PPARd) are a set of ligand-activated transcription factors in the nuclear hormone receptor superfamily. These receptors regulate the expression of a large number of genes involved in lipid metabolism and energy balance by binding to a DNA sequence termed PPAR response elements. The PPARg is predominantly expressed in adipose tissues, and plays a pivotal role in adipose differentiation, and the regulation of glucose and lipid homeostasis. The clinically useful thiazolidinedione (TZD) class of insulin sensitizers such as rosiglitazone and pioglitazone (Fig. 1) are potent PPARg agonists used in the treatment of Type 2 diabetes. TZDs are known to improve insulin resistance, which is a key underlying feature of Type 2 diabetes; however, the use of TZDs has been limited because of their serious side effects such as hepatic toxicity, weight gain and edema. Meanwhile, PPARa is highly expressed in metabolically active tissues such as the liver, heart and muscle, and regulates lipid homeostasis. PPARa agonists such as clofibrate (Fig. 1) have demonstrated the ability to reduce serum triglyceride and increase HDL cholesterol levels, and are being utilized as hypolipidemic agents. In addition, recent studies revealed that dual agonists of PPARa /g decrease the free triglyceride plasma concentration and increase plasma HDL concentration in an insulin-resistant animal model. Thus, many groups have ongoing research programs to identify more potent and less toxic PPARa agonists, PPARg agonists and PPARa /g dual agonists. We previously reported compound 1 (Fig. 1), which was designed based on the structure of rosiglitazone and 15dPGJ2, 12,13) as a potent PPARg ligand. To find more potent PPARg agonists and novel PPARa agonists, we chose compound 1 as the lead structure, because recent reports indicated that PPARg affinity can be increased by the introduction of substituents into the C-2 position of propanoic acid, and minor structural modifications can convert PPAR subtype selectivity. In this article, we report the synthesis, binding affinity and biological activity of PPAR ligands based on the structure of compound 1.