Current PPAR-gamma agonists have been found to improve insulin sensitivity however have significant adverse effects upon the heart.
We have developed based upon computational analysis selective PPAR-gamma agonists that lack interaction of the tyr473 in the ligand binding domain (AF2) of PPAR-gamma. Further our lead compound has been designed to display higher blood brain barrier activity and thus improved PPAR-gamma agonism in the brain. We have observed that our compounds improve behavior in severely diabetic mice (db/db, leptin deficient mice) and in models of Alzheimer's disease. Our studies have observed an increase in the neurotrphin BDNF and NGF expression in cell cultures as well as in the brain. |