During the last decade, peroxisome proliferator-activated receptor δ (PPARδ) has received great attention as a potential drug target for the prevention of the metabolic syndrome and type 2 diabetes. The beneficial biological effects of PPARδ activation are well established, and increases in the amount of high-density lipoprotein (HDL) and reverse cholesterol transport, as well as a decrease in plasma glucose. However, much remains to be discovered, and to date, there are no drugs on the market targeting this receptor.
Due to the beneficial effects of PPARδ activation, it is also of interest to investigate the effects of PPARδ antagonism, in order to further elucidate the biological role of PPARδ. This thesis therefore focused on the development of new high-affinity PPARδ antagonists.
In total, eleven compounds were prepared using GSK3787, a selective PPARδ antagonist, as the lead compound. The first-generation analogues, 7-16, were synthesized partly by a published route. An efficient approach was developed for the synthesis of the second-generation analogue 23. Molecular modelling studies indicate that 23 is the most potent of the synthesized compounds. Biological studies are currently ongoing.