Kataoka K, Shiota T, Takeyasu T, Minoshima T, Watanabe K, Tanaka H, Mochizuki T, Taneda K, Ota M, Tanabe H, Yamaguchi H
Teijin Institute for Bio-Medical Research, Tokyo, Japan.
J Med Chem. 1996 Mar 15;39(6):1262-70. doi: 10.1021/jm950828+.
Novel N-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)amide derivatives 1 were synthesized and tested for their ability to inhibit rabbit small intestinal ACAT (acyl-CoA:cholesterol acyltransferase) and lower serum total cholesterol in cholesterol-fed rats. Among the synthesized compounds, N-(2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl)amide derivatives showed potent ACAT inhibitory activity. The synthesis and structure-activity relationships of these compounds are described. A methyl group at position 6 of the 2,3-dihydrobenzofuran moiety was important for potent ACAT inhibitory activity. In the series of N-(2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl) amides, lipophilicity of the acyl moiety was necessary for the potent ACAT inhibitory activity. The highly lipophilic acid amides N-(2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl)-2,2- dimethyldodecanamide (10) and 6-(4-chlorophenoxy)-N-(2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-y l)-2,2-dimethyloctanamide (50) showed potent activity. Introduction of a dimethylamino group at position 5 of the 2,3-dihydrobenzofuran moiety resulted in highly potent activity. The most potent compound, N-[5-(dimethylamino)-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl ]-2,2-dimethyldodecanamide (13, TEI-6620), showed highly potent ACAT inhibitory activity (rabbit small intestine IC50 = 0.020 microM, rabbit liver IC50 = 0.009 microM), foam cell formation inhibitory activity (rat peritoneal macrophage IC50 = 0.030 microM), extremely potent serum cholesterol-lowering activity in cholesterol-fed rats (71% at a dose of 0.3 mg/kg/day po), and good bioavailability in fed dogs (Cmax = 2.68 microg/mL at 1 h, 10 mg/kg po).
合成了新型N-(2,2-二甲基-2,3-二氢苯并呋喃-7-基)酰胺衍生物1，并测试了它们抑制兔小肠酰基辅酶A：胆固醇酰基转移酶(ACAT)的能力以及降低胆固醇喂养大鼠血清总胆固醇的能力。在合成的化合物中，N-(2,2,4,6-四甲基-2,3-二氢苯并呋喃-7-基)酰胺衍生物显示出强效的ACAT抑制活性。描述了这些化合物的合成及其构效关系。2,3-二氢苯并呋喃部分6位上的甲基对于强效的ACAT抑制活性很重要。在N-(2,2,4,6-四甲基-2,3-二氢苯并呋喃-7-基)酰胺系列中，酰基部分的亲脂性对于强效的ACAT抑制活性是必需的。高亲脂性的酰胺N-(2,2,4,6-四甲基-2,3-二氢苯并呋喃-7-基)-2,2-二甲基十二烷酰胺(10)和6-(4-氯苯氧基)-N-(2,2,4,6-四甲基-2,3-二氢苯并呋喃-7-基)-2,2-二甲基辛酰胺(50)显示出强效活性。在2,3-二氢苯并呋喃部分5位引入二甲氨基导致活性极高。最有效的化合物N-[5-(二甲氨基)-2,2,4,6-四甲基-2,3-二氢苯并呋喃-7-基]-2,2-二甲基十二烷酰胺(13，TEI-6620)显示出极高的ACAT抑制活性(兔小肠IC50 = 0.020 microM，兔肝脏IC50 = 0.009 microM)、泡沫细胞形成抑制活性(大鼠腹膜巨噬细胞IC50 = 0.030 microM)、在胆固醇喂养大鼠中具有极强的血清胆固醇降低活性(口服剂量0.3 mg/kg/天时为71%)以及在喂食的狗中具有良好的生物利用度(Cmax = 2.68 microg/mL，1小时，口服10 mg/kg)。
