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

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 α-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. Res. 61:19–36, 2004. © 2004 Wiley-Liss, Inc.