Peroxisome proliferator-activated receptors (PPARs) belong to a family of nuclear receptors that control many cellular and metabolic processes. Three mammalian PPARs have been identified, i.e., PPARα, PPARδ, and PPARγ. See Lee C. H. et al., Endocrinology 2003, 144: 2201-7. Upon activation, PPARs trigger a cascade of transcriptional events leading to altered lipid and glucose metabolism. See, e.g., Willson T. M. et al., J Med Chem 2000, 43, 527-50; and Moraes L. A. et al., Pharmacol Ther. 2006, 110, 371-85.
Given their roles in lipid and glucose metabolism, PPARs are promising therapeutic targets of diseases, such as type II diabetes, obesity, hepatitis C, dyslipidemia, coronary heart disease, inflammatory disease, and cancer. For example, glitazones, PPARγ agonists, have been used to treat type II diabetes. As another example, fibrates, PPARα agonists, are effective medications that lower blood triglyceride levels. However, most PPAR therapeutics have limited efficacy or significant side effects.
There is still a need to develop more effective drugs for controlling lipid and glucose metabolism via modulation of PPAR activity.