Inhibitors of acyl-CoA:cholesterol acyltransferase. 1. Identification and structure-activity relationships of a novel series of fatty acid anilide hypocholesterolemic agents
作者:Bruce D. Roth、C. John Blankley、Milton L. Hoefle、Ann Holmes、W. Howard Roark、Bharat K. Trivedi、Arnold D. Essenburg、Karen A. Kieft、Brian R. Krause、Richard L. Stanfield
DOI:10.1021/jm00087a016
日期:1992.5
significant reductions in plasma total cholesterol in cholesterol-fed rats. Additionally, in vivo activity could be improved significantly by the introduction of alpha,alpha-disubstitution into the fatty acid portion of the molecule. A narrow group of alpha,alpha-disubstituted trimethoxyanilides, exemplified by 2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide (39), was found to not only lower plasma total
制备了一系列脂肪酸酐,并测试了化合物在体外抑制由胆固醇喂养的大鼠体内的酰基辅酶A:胆固醇酰基转移酶(ACAT)并降低血浆总胆固醇和升高高密度脂蛋白胆固醇的能力。体内。发现所报告的化合物分为两个亚类,具有不同的苯胺基比吸收率。对于非支链的酰基类似物,发现抑制效力最适合与庞大的2,6-二烷基取代。对于α-取代的酰基类似物,离体效力几乎不依赖于苯胺取代,并且2,4,6-三甲氧基是唯一优选的。发现大多数有效的抑制剂(IC50低于50 nM)可显着降低胆固醇喂养大鼠的血浆总胆固醇。另外,通过将α,α-二取代引入分子的脂肪酸部分可以显着改善体内活性。发现一小组狭窄的α,α-二取代的三甲氧基苯胺,例如2,2-二甲基-N-(2,4,6-三甲氧基苯基)十二碳酰胺(39),不仅降低了血浆总胆固醇(-60%),胆固醇喂养的大鼠,但在饮食中0.05%的筛查剂量(约50 mg / kg)下,该模型中的高密度脂蛋白胆固醇水平也升高(+