2-AZETIDINONE CHOLESTEROL ABSORPTION INHIBITORS - STRUCTURE-ACTIVITY-RELATIONSHIPS ON THE HETEROCYCLIC NUCLEUS

A series of azetidinone cholesterol absorption inhibitors related to S CH 48461 ((-)-6) has been prepared, and compounds were evaluated for t heir ability to inhibit hepatic cholesteryl ester formation in a chole sterol-fed hamster model. Although originally designed as acyl CoA: ch olesterol acyltransferase (ACAT) inhibitors, comparison of in vivo pot ency with in vitro activity in a microsomal ACAT assay indicates no co rrelation between activity in these two models, The molecular mechanis m by which these compounds inhibit cholesterol absorption is unknown. Despite this limitation, examination of tile in vivo activity of a ran ge of compounds has revealed clear structure-activity relationships co nsistent with a well-defined molecular target. The details of these st ructure-activity relationships and their implications on the nature of the putative pharmacophore are discussed.