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.
FY-087 (N-[2-[N'-pentyl-(6,6-dimethyl-2,4-heptadiynyl)amino]ethyl]- (2-methyl-1-naphthylthio)acetamide) was found to be a competitive inhibitor of human microsomal acyl coenzyme A:cholesterol acyltransferase (ACAT) with an IC50 value of 0.11 microM. 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 IC50 values of 0.18, 0.14, and 3.2 microM, respectively. FY-087 also inhibited ACAT in acetyl-low density lipoprotein loaded human macrophages (THP-1 cells) with an IC50 of 0.17 microM. Following the oral administration of FY-087 (30 mg/kg) to rats, the plasma concentration of FY-087 reached 0.42 microgram/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.
Nagata
Y
Y
Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Tsukuba, Japan.
Yonemoto
M
M
Iwasawa
Y
Y
Shimizu-Nagumo
A
A
Hattori
H
H
Sawazaki
Y
Y
Kamei
T
T
D000214:Acyl Coenzyme A / Q000037:antagonists & inhibitors*; D000818:Animals; D001161:Arteriosclerosis / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D002460:Cell Line / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism; D004036:Diet, Atherogenic; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D013853:Thioacetamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology
D000214:Acyl Coenzyme A; C092474:FY 087; D013853:Thioacetamide; D002784:Cholesterol; D002785:Sterol O-Acyltransferase