FCE-27677 - A NOVEL INHIBITOR OF ACYL-COA-CHOLESTEROL ACYLTRANSFERASEWITH POTENT ORAL HYPOLIPIDEMIC ACTIVITY

FCE 27677 )phenyl]-N'-[(4R,5R)-2-(4-dimethylaminophenyl)-4,5 dimethyl- dioxolan-2-yl]methylurea) is a new systemically available ACAT inhibit or belonging to the class of ketalic disubstituted ureas. When tested in microsomes from rabbit intestine, aorta and liver, it inhibited the enzyme with IC50 of 9.31, 6.99 and 92.2 nM, respectively. It had no e ffect on plasma LCAT and intestinal cytosolic cholesterol esterases an d, when tested in a tissue culture system, it did not interfere with t he synthesis of cholesterol, triglycerides, and phospholipids. Enzyme inhibition kinetics indicated that FCE 27677 is a non-competitive inhi bitor of the enzyme with respect to acylCoA and to cholesterol. When a dministered mixed to a 1.5% cholesterol and 0.5% sodium cholate-enrich ed diet to rats, it prevented the development of hypercholesterolemia with ED(50) Of 0.35 mg kg(-1) day(-1). Given in a single oral dose to hypercholesterolemic rats it significantly reduced both the plasma lip id levels and the hepatic cholesteryl ester content within 6 h from ga vage. VLDL and LDL levels and composition were also significantly affe cted. Similar effects were observed when the drug was given mixed to a regular chow diet for 4 weeks to hypercholesterolemic rabbits. These results are consistent with the idea that systemically available ACAT inhibitors can affect the composition and the metabolism of the athero genic cholesteryl ester-rich VLDL and LDL. ACAT inhibitors appear prom ising for the correction of dyslipoproteinemias secondary to lipoprote in overproduction, and in reducing the atherogenic index of apoB-100 c ontaining lipoproteins. (C) 1995 The Italian Pharmacological Society