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.