Design of new potent hypolipidemic agents with the synergistic structural properties of α-asarone and fibrates

The series of bioisosteric analogs 9-17 were designed based on the potential pharmacophores of the highly hypolipidemic agents, α-asarone (1), and fibrates such as clofibrate (2) and fenofibrate (3). These compounds are characterized by their simplicity, in terms of functional group diversity, because most of them are phenoxyacetic acids or their methyl and ethyl esters monosubstituted by an ethyl side-chain at the ortho, meta, and para positions of the benzene ring. Despite this structural simplicity, these derivatives exhibited potent hypocholesterolemic activity, lowering the mice serum cholesterol and low-density lipoprotein cholesterol levels up to 40% at the lowest dose of 25 mg/kg. These results supported the concept that the phenoxyacetic frame and the ethyl side-chain can be considered as potent pharmacophores for the preparation of potential hypocholesterolemic drugs.