IMIDAZOLYLBENZOPYRANE DERIVATIVES - A NEW CLASS OF ACYL-COA - CHOLESTEROL ACYLTRANFERASE (ACAT) INHIBITORS

Inhibitors of the enzyme Acyl-CoA: Cholesterol Acyltransferase are reg arded as potentially useful agents in the treatment of hypercholestero lemia and atherosclerosis. We report here a novel series of 2, 6-disub stituted-3-imidazolylbenzopyrane derivatives with significant in vitro ACAT inhibitory activity (IC50 range 0.05-0.5 mu M) Compounds of this series such as 26 are examples of a new, structurally distinct class of potent ACAT inhibitors with high specificity for the aortic subtype of the enzyme. The structure-activity relationships of the 3-imidazol ylbenzopyrane ACAT inhibitors were investigated by systematic manipula tion of two regions of the parent compound 1 and the inhibitory activi ty resulted linked to the substituent in position 6 of the benzopyrane ring and modulated by the size of lipophilic substituents in position 2. Investigation of the mechanism of the inhibitory effect leads to t he conclusion that these compounds act in a non-competitive fashion.