ACAT Inhibitors: Potential Anti-atherosclerotic Agents

Abstract

Abstract: The evolution of ACAT inhibitors •from purely hypocholestero­ lemic agents to potential anti-atherosclerdtic agents has occurred only recently.A large number of structurally diverse ACAT inhibitors were initially developed as hypocholesterolemic agets whose prime mechanism of action was inhibition of dietary cholesterol absorption in the intestine, however, efficacy for such non-absorbable agents, in humans, has remained elusive. Esterification of cholesterol within the hepatocyte has been shown to be required for VLDL synthesis and secretion, and inhibition of ACAT within the artery wall may prove to be the "ultimate" anti-atherosclerotic mechanism by preventing the formation of cholesterol ester loaded macrophages (foam cells), the precursors of the fatty streak, an early lesion in the atherosclerotic process. Thus, more recently, there has been a concerted effort to design more bioavailable inhibitors capable of inhibiting the enzyme in the liver and artery wall. Displaying direct efficacy at the artery wall for an ACAT inhibitor has been complicated by the fact that in pre-clinical animal models, it has been difficult to dissociate the effects of lipid lowering from a true direct effect at the artery wall. Recently, a novel ACAT inhibitor, Cl-976, has been disclosed which displays anti-atherosclerotic activity in an injured cholesterol fed rabbit model of atherosclerosis without exhibiting a cholesterol lowering effect.The SAR around Cl-976 and related series will be discussed and placed in context with other novel structural types of ACAT inhibitors appearing in the recent literature.