Ogino Masaki, Fukui Seiji, Nakada Yoshihisa, Tokunoh Ryosuke, Itokawa Shigekazu, Kakoi Yuichi, Nishimura Satoshi, Sanada Tsukasa, Fuse Hiromitsu, Kubo Kazuki, Wada Takeo, Marui Shogo
Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Kanagawa, Japan.
Chem Pharm Bull (Tokyo). 2011;59(10):1268-73. doi: 10.1248/cpb.59.1268.
Acyl-CoA: cholesterol acyltransferase (ACAT) is an intracellular enzyme that catalyzes cholesterol esterification. ACAT inhibitors are expected to be potent therapeutic agents for the treatment of atherosclerosis. A series of potent ACAT inhibitors based on an (4-phenylcoumarin)acetanilide scaffold was identified. Evaluation of the structure-activity relationships of a substituent on this scaffold, with an emphasis on improving the pharmacokinetic profile led to the discovery of 2-[7-chloro-4-(3-chlorophenyl)-6-methyl-2-oxo-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide (23), which exhibited potent ACAT inhibitory activity (IC50=12 nM) and good pharmacokinetic profile in mice. Compound 23 also showed regressive effects on atherosclerotic plaques in apolipoprotein (apo)E knock out (KO) mice at a dose of 0.3 mg/kg per os (p.o.).
酰基辅酶A：胆固醇酰基转移酶（ACAT）是一种催化胆固醇酯化的细胞内酶。ACAT抑制剂有望成为治疗动脉粥样硬化的有效治疗药物。已鉴定出一系列基于（4-苯基香豆素）乙酰苯胺支架的强效ACAT抑制剂。对该支架上取代基的构效关系进行评估，重点是改善药代动力学特征，从而发现了2-[7-氯-4-（3-氯苯基）-6-甲基-2-氧代-2H-色烯-3-基]-N-[4-氯-2-（三氟甲基）苯基]乙酰胺（23），其在小鼠中表现出强效的ACAT抑制活性（IC50 = 12 nM）和良好的药代动力学特征。化合物23在载脂蛋白（apo）E基因敲除（KO）小鼠中以0.3 mg/kg口服（p.o.）剂量给药时，对动脉粥样硬化斑块也显示出消退作用。
