N-[2-[N'-PENTYL-(6,6-DIMETHYL-2,4-HEPTADIYNYL) AMINO]ETHYL]-(2-METHYL-1-NAPHTHYLTHIO)ACETAMIDE (FY-087) - A NEW ACYL-COENZYME A-CHOLESTEROLACYLTRANSFERASE (ACAT) INHIBITOR OF DIET-INDUCED ATHEROSCLEROSIS FORMATION IN MICE

FY-087 )amino]ethyl]-(2-methyl-1-naphthyl-thio)acetamide) was found to be a competitive inhibitor of human microsomal acyl coenzyme A:choles terol acyltransferase (ACAT) with an IC50 value of 0.11 mu M. Under ou r assay conditions, other ACAT inhibitors tested, specifically YM-750, E-5324, and melinamide, all of which are now in phase I clinical tria ls or in clinical use in Japan, inhibited this enzyme with IC50, value s of 0.18, 0.14, and 3.2 mu M, respectively. FY-087 also inhibited ACA T in acetyl-low density lipoprotein loaded human macrophages (THP-1 ce lls) with an IC50 of 0.17 mu M. Following the oral administration of F Y-087 (30 mg/kg) to rats, the plasma concentration of FY-087 reached 0 .42 mu g/mL after 2 hr. This concentration of FY-087 was enough to inh ibit blood vessel ACAT activity. Cholesterol-lowering and anti-atherog enic effects of FY-087 were examined using C57BL/6J mice fed an athero genic diet. In this mouse model, treatment with FY-087 (28 mg/kg) inhi bited the increase in plasma cholesterol levels by about 20% and decre ased the hepatic accumulation of free and esterified cholesterol by 61 and 67%, respectively. FY-087 also significantly inhibited the athero genic diet-induced increase in the fatty-streak lesion area of the pro ximal aorta by 57% in C57BL/6J mice. These results indicate that FY-08 7 is not only a therapeutically bioavailable ACAT inhibitor that lower s plasma cholesterol levels, but also an effective anti-atherogenic ag ent in mice fed an atherogenic diet.