N-[2-[ N′-pentyl-(6,6-dimethyl-2,4-heptadiynyl) amino]ethyl]-(2-methyl-1-naphthylthio)acetamide (FY-087) : A new acyl coenzyme A:Cholesterol acyltransferase (ACAT) inhibitor of diet-induced atherosclerosis formation in mice

Abstract

FY-087 ( N-[2-[ N′-pentyl-(6,6-dimethyl-2,4-heptadiynyl)amino]ethyl]-(2-methyl-1-naphthyl-thio)acetamide) was found to be a competitive inhibitor of human microsomal acyl coenzyme A:cholesterol acyltransferase (ACAT) with an ic 50 value of 0.11 μM. Under our assay conditions, other ACAT inhibitors tested, specifically YM-750, E-5324, and melinamide, all of which are now in phase I clinical trials or in clinical use in Japan, inhibited this enzyme with ic 50 values of 0.18, 0.14, and 3.2 μM, respectively. FY-087 also inhibited ACAT in acetyl-low density lipoprotein loaded human macrophages (THP-1 cells) with an ic 50 of 0.17 μM. Following the oral administration of FY-087 (30 mg/ kg) to rats, the plasma concentration of FY-087 reached 0.42 μg/mL after 2 hr. This concentration of FY-087 was enough to inhibit blood vessel ACAT activity. Cholesterol-lowering and anti-atherogenic effects of FY-087 were examined using C57BL/6J mice fed an atherogenic diet. In this mouse model, treatment with FY-087 (28 mg/kg) inhibited the increase in plasma cholesterol levels by about 20% and decreased the hepatic accumulation of free and esterified cholesterol by 61 and 67%, respectively. FY-087 also significantly inhibited the atherogenic diet-induced increase in the fatty-streak lesion area of the proximal aorta by 57% in C57BL/6J mice. These results indicate that FY-087 is not only a therapeutically bioavailable ACAT inhibitor that lowers plasma cholesterol levels, but also an effective anti-atherogenic agent in mice fed an atherogenic diet.