Kogushi M, Tanaka H, Kobayashi H, Yamada T, Ohtsuka I, Kimura T, Saito I
Eisai Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
Jpn J Pharmacol. 1995 Jun;68(2):191-9. doi: 10.1254/jjp.68.191.
The in vitro potencies of a novel inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT), E5324 (n-butyl-N'-[2-[3-(5-ethyl-4-phenyl-1H-imidazol-1-yl)propoxy]-6- methylphenyl]urea), were studied. E5324 was found to be a potent ACAT inhibitor in microsomes from a various tissues and in cultured cell homogenate, with IC50 values in the range of 0.044 to 0.19 microM. The kinetic study on E5324 showed that the inhibition of rat intestine ACAT was competitive with respect to oleoyl CoA. E5324 inhibited [3H]olate incorporation into cholesteryl [3H]oleate in phorbol ester-treated THP-1 cell lines (IC50 = 0.44 microM). The rate of [3H]oleate incorporation into phospholipids and triglycerides was not affected by E5324. In an experiment with [3H]cholesterol as the substrate for ACAT, E5324 also inhibited [3H]cholesteryl ester synthesis (IC50 = 0.41 microM). Furthermore, E5324 prevented accumulation of both esterified and total cholesterol in acetyl low density lipoprotein-loaded THP-1 cells. These results indicate that E5324 is a potent and selective ACAT inhibitor and prevents cholesteryl ester accumulation in macrophages.
对新型酰基辅酶A：胆固醇酰基转移酶（ACAT）抑制剂E5324（正丁基 - N'-[2 - [3 - (5 - 乙基 - 4 - 苯基 - 1H - 咪唑 - 1 - 基)丙氧基]-6 - 甲基苯基]脲）的体外效力进行了研究。发现E5324在来自各种组织的微粒体和培养细胞匀浆中是一种有效的ACAT抑制剂，IC50值在0.044至0.19微摩尔范围内。对E5324的动力学研究表明，其对大鼠肠道ACAT的抑制作用相对于油酰辅酶A是竞争性的。E5324抑制佛波酯处理的THP - 1细胞系中[3H]油酸掺入胆固醇[3H]油酸酯（IC50 = 0.44微摩尔）。[3H]油酸掺入磷脂和甘油三酯的速率不受E5324影响。在以[3H]胆固醇作为ACAT底物的实验中，E5324也抑制[3H]胆固醇酯合成（IC50 = 0.41微摩尔）。此外，E5324可防止乙酰低密度脂蛋白负载的THP - 1细胞中酯化胆固醇和总胆固醇的积累。这些结果表明E5324是一种有效且选择性的ACAT抑制剂，并可防止巨噬细胞中胆固醇酯的积累。
