The synthesis of three isotopomers of 2-methyl-2-(4-(3-(1-(4-methylbenzyl)-5-oxo-4,5-dihydro-lH-(l,2,4)triazol-3-yl)propyl)phenoxy)propionic acid, a potent and selective peroxisome proliferator-activated receptor alpha agonist

摘要

Although fenofibrate (la) is commercially available and clinically effective in lowering serum triglycerides, its activity and sub-type selectivity at the PPARa receptors are only moderate; therefore, there exists a need for more potent and sub-type selective PPARa agonists. To that end, discovery efforts have identified 2-methyl-2-(4-[3-[l-(4-methylbenzyl)-5-oxo-4,5-dihydro-lH-[l,2,4]triazol-3-yl]propyl]phenoxy)propionic acid (2), a potent and selective human PPARa receptor agonist. In support of pre-clinical ADME studies and bioanalysis, three isotopomers of 2 have been synthesized. The results of these efforts are described below.