Tanaka A, Terasawa T, Hagihara H, Sakuma Y, Ishibe N, Sawada M, Takasugi H, Tanaka H
Medicinal Chemistry Research Laboratories, Fujisawa Pharmaceutical Co. Ltd., Osaka, Japan.
Bioorg Med Chem. 1998 Jan;6(1):15-30. doi: 10.1016/s0968-0896(97)10009-8.
A series of N-alkyl-N-biphenylylmethyl-N'-arylurea and related derivatives represented by 1 have been prepared and evaluated for their ability to inhibit acyl-CoA:cholesterol O-acyltransferase in vitro and to lower plasma cholesterol levels in cholesterol-fed rats in vivo. Linking of two phenyl groups via oxygen and introduction of fluorine at appropriate positions on the biphenyl moiety improved in vitro and in vivo activity. From this series of analogs, compound 40 (FR179254), which had potent in vitro potency (rabbit intestinal microsomes IC50 = 25 nM), showed excellent plasma cholesterol-lowering activity when administered via the diet (ED50 = 0.045 mg/kg). However, the hypocholesterolemic effect of this compound was moderate when dosed by oral gavage in PEG400 as a vehicle (ED50 = 5.3 mg/kg). Modification of the N'-aryl moiety led to the identification of compound 50 (FR182980) which was efficacious in both dosing models (ED50 = 0.034 mg/kg and 0.11 mg/kg, respectively).
已经制备了一系列由1表示的N-烷基-N-联苯甲基-N'-芳基脲及其相关衍生物，并评估了它们在体外抑制酰基辅酶A：胆固醇O-酰基转移酶的能力以及在体内降低胆固醇喂养大鼠血浆胆固醇水平的能力。通过氧连接两个苯基并在联苯部分的适当位置引入氟可提高体外和体内活性。在这一系列类似物中，化合物40（FR179254）具有强大的体外效力（兔肠微粒体IC50 = 25 nM），通过饮食给药时显示出优异的降低血浆胆固醇活性（ED50 = 0.045 mg/kg）。然而，当以聚乙二醇400作为载体通过口服灌胃给药时，该化合物的降胆固醇作用中等（ED50 = 5.3 mg/kg）。对N'-芳基部分的修饰导致鉴定出化合物50（FR182980），其在两种给药模型中均有效（ED50分别为0.034 mg/kg和0.11 mg/kg）。
