Tawada H, Harcourt M, Kawamura N, Kajino M, Ishikawa E, Sugiyama Y, Ikeda H, Meguro K
Pharmaceutical Research Laboratories II, Takeda Chemical Industries, Ltd., Osaka, Japan.
J Med Chem. 1994 Jun 24;37(13):2079-84. doi: 10.1021/jm00039a020.
A series of 3-quinolylurea derivatives (1) was synthesized and evaluated for acyl-CoA:cholesterol acyltransferase (ACAT) inhibitory activity. For in vitro studies, the most potent inhibitory activity was found in derivatives having substituents at the 6,7- or 6,8-positions and an ortho-substituted phenyl group at the 4-position of quinoline ring. The 2,4-difluorophenyl group appeared to be the optimum N'-substituent of the urea moiety. The IC50 values of compounds 52-54 and 59 were in the nanomolar order. Plasma cholesterol-lowering activity of compounds 50, 52, and 54 was observed at less than 1 mg/kg/day in cholesterol-fed rats. Compound 52 was also hypocholesterolemic in hamsters fed a diet without loading cholesterol.
合成了一系列3-喹啉基脲衍生物（1），并对其酰基辅酶A：胆固醇酰基转移酶（ACAT）抑制活性进行了评估。在体外研究中，在喹啉环4位具有6,7-或6,8-位取代基和邻位取代苯基的衍生物中发现了最强的抑制活性。2,4-二氟苯基似乎是脲部分的最佳N'-取代基。化合物52 - 54和59的IC50值处于纳摩尔级别。在喂食胆固醇的大鼠中，观察到化合物50、52和54在低于1mg/kg/天的剂量下具有降低血浆胆固醇的活性。在喂食不含胆固醇饲料的仓鼠中，化合物52也具有降胆固醇作用。
