Potent hypolipidemic activity of mimetic amides of fibrates based on the 2‐methoxy‐4‐(2‐propenyl)phenoxyacetic scaffold

Abstract

A series of bioisosteric analogues of fibrates, such as clofibrate (2) and bezafibrate (3), was designed, considering the pharmacophore potential of phenoxyacetic derivatives 4 related to a-asarone (1) in their structure. Thus, the hypolipidemic activity of the series of amides 5a-5j, 6a-6d, and 7a-7c, amines 8b-8d, and amino acids 9a-9e has been evaluated. A significant decrease in serum cholesterol was observed in mice for a number of these compounds. Some of them also showed a lowering of low-density lipoprotein cholesterol, and a few had an effect on increasing the high-density lipoprotein cholesterol levels, and on reducing the triglyceride serum contents. Phenoxyacetic, phenoxyethyl-amido and -amino moieties, as well as the presence of a chlorine atom in their aromatic rings, were identified as potential pharmacophores. Unexpectedly, derivatives 9a-9e, bearing an amino acid group, did not exhibit any hypolipidemic activity under a similar pharmacological protocol. Drug Dev.

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

“…Besides the introduction of the phenoxyacetic moiety, these analogues maintained some structural features of the previously prepared analogues of 1, such as the unconjugated propenyl side-chain [Chamorro et al, 1998], and the methoxy or nitro groups [Díaz et al, 1993]. Recently, a number of fibrate mimetic amides were prepared and evaluated biologically, showing a decrease of serum cholesterol and a lowering of low-density lipoprotein (LDL) cholesterol [Hernández et al, 2004].…”

Synthesis and Biological Evaluation of Orally Active Hypolipidemic Agents

“…This pleiotropic effect of the fenofibrate contributes in their coronary risk-reducing ability. − Moreover, several studies indicate that fibrates decrease the level of factors promoting coagulation and increase fibrinolysis. The dual hypolipidemic/antiplatelet effect of fibrates renders them interesting candidates for reducing the risk of atherosclerosis and its thrombotic complications, which are the major causes of coronary artery diseases. , α-Asorane bioisosteric analogues of fibrates such as clofibrate, bezafibrate, and fenofibrate have significant hypocholesterolaemic activity. − These interesting findings motivates us to prepare new fenofibric acid ester prodrugs 1c – 1h that might hold promising hypolipidemic activity.…”

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

“…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). Phenoxyacetic acids 7 have been reported to exhibit antimicrobial, herbicidal, and low and moderate fungicidal activities (Nair and Burke, 1988;Zawadowska, 1962Zawadowska, , 1963Suyama and Kato, 1989;Purohit and Shah, 1999;Arcamone et al, 1957).…”