Hypolipidemic Activity of New Phenoxyacetic Derivatives Related to α-Asarone with Minimal Pharmacophore Features

Five new series of potential hypolipidemic agents 3-7 were synthesized, in order to establish the minimal pharmacophore features associated to the potent hypocholesterolemic activity of natural α-asarone (1) and synthetic clofibrate mimetic derivatives 2. The compounds were examined in hyperlipidemic male mice after oral administration of 25, 50, and 100 mg/Kg for 6 days. The isomeric series of acids and esters 3a-3c and 4a-4c were unexpectedly less active than the most simple structural isomeric compounds 5-7. This reveals that the phenoxyacetic acid scaffold carrying a hydrocarbon side chain, also found in derivatives 2, seems to be the most favorable lead for further development of potent hypolipidemic drugs.