Abstract: P715 EVEROLIMUS INHIBITS MONOCYTE MIGRATION AND THEIR ACCUMULATION IN CAROTID LESIONS OF CHOLESTEROL-FED RABBITS

Abstract

This chapter highlights CI-1011, which is a potent hypocholesterolemic and antiatherosclerotic agent. The enzyme acyl coenzyme A: cholesterol O-acyltransferase (ACAT) is the enzyme responsible for esterifying cholesterol utilizing CoA-activated fatty acid as substrate. Inhibition of this enzyme in the intestinal mucosal cell may provide a novel therapy for hypercholesterolemia by preventing the absorption of dietary cholesterol. ACAT inhibitors are all lipophilic with CLOGP values well above 6 and little aqueous solubility. ACAT catalyzes the esterification of massive amounts of cholesterol resulting in the formation of foam cells, an early precursor to the fatty streak. Inhibition of ACAT in monocyte–macrophages of the arterial wall is the major strategy in the field of atherosclerosis prevention, since direct inhibition of arterial ACAT may reduce the formation of macrophage-enriched fatty streaks and contribute to plaque stabilization by direct lipid depletion. CI-1011 is efficacious in a variety of cholesterol-fed and non-cholesterol-fed animal models. It is more potent than CI-999 in most of the cholesterol-fed models designed to show hypocholesterolemic activity. CI-1011 is screened against a variety of other enzymes involved in cholesterol metabolism.