Harris N V, Smith C, Ashton M J, Bridge A W, Bush R C, Coffee E C, Dron D I, Harper M F, Lythgoe D J, Newton C G
Rhone-Poulenc Rorer, Central Research, Dagenham, Essex, U.K.
J Med Chem. 1992 Nov 13;35(23):4384-92. doi: 10.1021/jm00101a016.
A potent, bioavailable ACAT inhibitor may have beneficial effects in the treatment of atherosclerosis by (i) reducing the absorption of dietary cholesterol, (ii) reducing the secretion of very low density lipoproteins into plasma from the liver, and (iii) preventing the transformation of arterial macrophages into foam cells. We have found that a mevalonate derivative 2, which contains a 4,5-diphenyl-1H-imidazol-2-yl moiety, inhibits rat hepatic microsomal ACAT in vitro and produces a significant hypocholesterolemic effect in the cholesterol-fed rat. Structure-activity relationships for analogues of 2 demonstrate that the 4,5-diphenyl-1H-imidazole moiety is a pharmacophore for inhibition of rat microsomal ACAT.
一种强效、可生物利用的酰基辅酶A：胆固醇酰基转移酶（ACAT）抑制剂可能通过以下方式对动脉粥样硬化的治疗产生有益效果：（i）减少膳食胆固醇的吸收；（ii）减少肝脏极低密度脂蛋白分泌到血浆中；以及（iii）防止动脉巨噬细胞转变为泡沫细胞。我们发现一种含有4,5 - 二苯基 - 1H - 咪唑 - 2 - 基部分的甲羟戊酸衍生物2在体外可抑制大鼠肝微粒体ACAT，并在喂食胆固醇的大鼠中产生显著的降胆固醇作用。2的类似物的构效关系表明，4,5 - 二苯基 - 1H - 咪唑部分是抑制大鼠微粒体ACAT的药效基团。
