PHARMACOLOGICAL PROPERTIES OF A NOVEL ACAT INHIBITOR (CP-113,818) IN CHOLESTEROL-FED RATS, HAMSTERS, RABBITS, AND MONKEYS

The novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor CP-113 ,818 has been characterized in vitro against ACAT isolated from liver and intestine from a variety of species including human subjects, and in vivo in cholesterol-fed rats, hamsters, rabbits, and two species of nonhuman primates. CP-113,818 is a potent and specific inhibitor of l iver and intestinal ACAT with IC(50)s ranging from 17 to 75 nM. This A CAT inhibitor also prevented the absorption of exogenous radiolabeled cholesterol in hamsters (ED(50) = 6 mu g/kg), rabbits (ED(50) 1/2 10 m u g/kg), and cynomolgus and African green monkeys (40 and 26% inhibiti on at 10 mg/kg, respectively). CP-113,818 effectively prevented the in crease in liver cholesterol levels in cholesterol-fed rats, hamsters, and rabbits. In lipoprotein characterization studies in rabbits, CP-11 3,818 selectively decreased apoB-containing lipoproteins (beta-VLDL, I DL, and LDL) and shifted the distribution of cholesterol from beta-VLD L, IDL, and LDL (96% before treatment to 81% after treatment) to HDL ( 4% before treatment to 19% after treatment). Finally, in monkeys, CP-1 13,818 significantly decreased LDL cholesterol by approximately 30% wh ile either increasing HDL cholesterol (cynomolgus monkeys) or not affe cting HDL cholesterol (African green monkeys), thereby improving the t otal plasma cholesterol/HDL ratios. In summary, CP-113,818 significant ly inhibited cholesterol absorption, prevented the increase in liver c holesterol, and improved the lipoprotein profiles by selectively decre asing the cholesterol concentrations of the atherogenic lipoproteins ( VLDL, IDL, and LDL) in a variety of cholesterol-fed animals. These dat a suggest that ACAT inhibition may be a useful therapeutic approach fo r lowering LDL cholesterol and thereby reducing the risk of developing coronary heart disease.