Kataoka K, Shiota T, Takeyasu T, Mochizuki T, Taneda K, Ota M, Tanabe H, Yamaguchi H
Teijin Institute for Bio-Medical Research, Tokyo, Japan.
J Med Chem. 1995 Aug 4;38(16):3174-86. doi: 10.1021/jm00016a021.
Novel N-(4-oxochroman-8-yl)amide derivatives 1 were synthesized and tested for their ability to inhibit rabbit small intestinal ACAT (acyl-CoA:cholesterol acyltransferase) in vitro and to lower serum total cholesterol in cholesterol-fed rats in vivo. Among the synthesized compounds, N-(7-alkoxy-4-oxochroman-8-yl)amide derivatives showed potent ACAT inhibitory activity both in vitro and in vivo. The structure-activity relationships of these N-(4-oxochroman-8-yl)amides and related compounds are discussed on the basis of these two assays. The carbonyl group at position 4 of the 4-chromanone was essential for potent ACAT inhibitory activity. N-(Chromon-8-yl) derivatives were less potent than N-(4-oxochroman-8-yl) derivatives. An alkoxy group at position 7 of the 4-chromanone moiety was important for potent ACAT inhibitory activity. In the N-(7-alkoxy-4-oxochroman-8-yl)amide derivatives, another necessary factor to elicit the potent ACAT inhibitory activity was lipophilicity of the molecules. The highly lipophilic acid amides N-(7-methoxy-4-oxochroman-8-yl)-2,2-dimethyldodecanamide (35) and 4-[[6-(4-chlorophenoxy)hexyl]oxy]-N-(7-methoxy-4-oxochroman-8- yl)benzamide (63) showed potent activity. Introduction of a highly lipophilic alkoxy group at position 7 of the 4-chromanone moiety instead of methoxy group also resulted in potent activity. In this case, highest inhibitory activity was obtained by N-[7-(decyloxy)-4-oxochroman-8-yl]-2,2-dimethylpropanamid e (65). The most potent compound, N-(7-methoxy-4-oxochroman-8-yl)-2,2-dimethyldodecanamide (35, TEI-6522), showed significant ACAT inhibitory activity (rabbit small intestine IC50 = 13 nM, rabbit liver IC50 = 16 nM), foam cell formation inhibitory activity (rat peritoneal macrophage IC50 = 160 nM), and extremely potent serum cholesterol-lowering activity in cholesterol-fed rats (61% at a dose of 0.1 mg/kg/day po).
合成了新型N-(4-氧代色满-8-基)酰胺衍生物1，并测试了它们在体外抑制兔小肠酰基辅酶A：胆固醇酰基转移酶(ACAT)以及在体内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-(7-烷氧基-4-氧代色满-8-基)酰胺衍生物在体外和体内均表现出较强的ACAT抑制活性。基于这两种测定方法，讨论了这些N-(4-氧代色满-8-基)酰胺及相关化合物的构效关系。4-色满酮4位的羰基对于有效的ACAT抑制活性至关重要。N-(色满-8-基)衍生物的活性低于N-(4-氧代色满-8-基)衍生物。4-色满酮部分7位的烷氧基对于有效的ACAT抑制活性很重要。在N-(7-烷氧基-4-氧代色满-8-基)酰胺衍生物中，引发有效ACAT抑制活性的另一个必要因素是分子的亲脂性。高亲脂性的酰胺N-(7-甲氧基-4-氧代色满-8-基)-2,2-二甲基十二烷酰胺(35)和4-[[6-(4-氯苯氧基)己基]氧基]-N-(7-甲氧基-4-氧代色满-8-基)苯甲酰胺(63)表现出较强的活性。在4-色满酮部分7位引入高亲脂性的烷氧基而非甲氧基也产生了较强的活性。在这种情况下，N-[7-(癸氧基)-4-氧代色满-8-基]-2,2-二甲基丙酰胺(65)具有最高的抑制活性。最有效的化合物N-(7-甲氧基-4-氧代色满-8-基)-2,2-二甲基十二烷酰胺(35，TEI-6522)表现出显著的ACAT抑制活性(兔小肠IC50 = 13 nM，兔肝脏IC50 = 16 nM)、泡沫细胞形成抑制活性(大鼠腹膜巨噬细胞IC50 = 160 nM)以及在胆固醇喂养大鼠中极强的血清胆固醇降低活性(口服剂量0.1 mg/kg/天时为61%)。
