Hypocholesterolemic Action and Prevention of Cholesterol Absorption via the Gut by F-1394, a Potent Acyl-CoA:Cholesterol Acyltransferase (ACAT) Inhibitor, in Cholesterol Diet-Fed Rats

The Japanese Journal of Pharmacology

Sakiko Higashinakagawa¹  Haruo Ohnishi¹  Jun Kusunoki¹  Tetsuya Kitamine¹  Katsumi Aragane¹  Noriko Kase¹  Tetsuaki Yamaura¹ 

[1]Pharmaceuticals Research Laboratories, Fujirebio, Inc.

关键词: F-1394;    Acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor;    Cholesterol absorption;    Hypocholesterolemic action;    Cholesterol-fed rat;   

DOI  :  10.1254/jjp.69.53

学科分类：药理学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(28)Cited-By(6)In the present study, we investigated the hypocholesterolemic effect of F-1394 ((ls, 2s)-2-[3-(2, 2-dimethylpropyl)-3-nonylureido]aminocyclohexane-1-yl 3-[N-(2, 2, 5, 5-tetramethyl-1, 3-dioxane-4-carbonyl)amino]propionate), a potent and selective inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT), and the effect on cholesterol absorption via the gut in rats fed a 1 % cholesterol diet. Single administration of F-1394 to the cholesterol diet-fed rats at the doses of 3-30 mg/kg, p.o. decreased the serum cholesterol levels by 16 - 54% 3 hr after the administration. The ACAT activity in the small intestinal mucosa of the rats given orally F-1394 (30 mg/kg) was significantly inhibited 3 hr after the administration. The hypocholesterolemic action of F-1394 had a faster onset than that of DL-melinamide or CL-277, 082. The study by the dual isotope ratio method showed that F-1394 (30 mg/kg, p.o.) significantly suppressed the dietary cholesterol absorption. Furthermore, in the determination of cholesterol absorption by using 14C-cholesterol as the oral tracer, the administration of F-1394 (30 mg/kg, p.o.) 1 or 2 hr before or immediately after the application of the oral tracer significantly prevented the appearance of the radioactivity in the circulation by around 90%. These results indicate that oral administration of F-1394 inhibits the ACAT activity in the small intestinal mucosa and subsequently contributes much to the prevention of cholesterol absorption via the gut, resulting in the decrease in serum cholesterol levels in the cholesterol diet-fed rats. Furthermore, the effect of F-1394 appears immediately after its administration in contrast to that of DL-melinamide or CL-277, 082.

【 授权许可】

Unknown