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

Abstract

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 a-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. Drug Dev.

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

“…Unlike the isomeric compounds 8 [Cruz et al, 2003], the ortho, meta, and para ethyl-and acetylphenoxyacetic acids and esters 9-11 and 12-14, respectively, show a quite similar potency. Because of their structural simplicity and size, it is possible that their pharmacokinetic behavior and binding to the active site are not largely modified by changes in the position of the pharmacophores.…”

“…Compounds 9a-9c, 10a-10c, and 11a-11c proved to be more potent hypocholesterolemic agents than their analogues 8 [Cruz et al, 2003], in which a methyl group takes over the place of the side-chain of derivatives 5. Hence, this result suggests that the optimum length of the side-chain, for the best biological effect, should be of two carbon atoms, substituting the propenyl side-chain of 1.…”

“…5) [Cruz et al, 2003]. Esterification of each acid to its methyl and ethyl esters was carried out by reacting methyl and ethyl alcohols in the presence of catalytic amounts of p-toluenesulfonic acid, to yield compounds 9b-9c, 10b-10c, and 11b-11c, respectively, in good yields (70-82%).…”

“…In order to establish the minimal pharmacophore features associated with the hypolipidemic activity of these potential drugs, we described the synthesis and biological evaluation of several series of compounds, containing only a few substituents in the benzene ring [Cruz et al, 2003]. Thus, the phenoxyacetic acid derivatives 6-8 (Fig.…”

Aryloxyacetic esters structurally related to α-Asarone as potential antifungal agents

“…We have reported that phenoxyacetic acids and esters 6, which take advantage of some structural pharmacophoric features of both a-Asarone (1) (Chamorro et al, 1998;Díaz et al, 1993) and fibrates, displayed a significant hypocholesterolemic activity (Labarrios et al, 1999;Cruz et al, 2003;Zúñiga et al, 2005). Recently, a number of fibrate mimetic amides, which were prepared and evaluated biologically, showed a decrease of serum cholesterol and a lowering of low-density lipoprotein (LDL) cholesterol (Hernández et al, 2004).…”