Batt D G, Maynard G D, Petraitis J J, Shaw J E, Galbraith W, Harris R R
Medical Products Department, E. I. du Pont de Nemours and Company, Inc., Wilmington, Delaware 19880-0353.
J Med Chem. 1990 Jan;33(1):360-70. doi: 10.1021/jm00163a058.
The synthesis, biological evaluation, and structure-activity relationships of a series of 1-naphthols bearing carbon substituents at the 2-position are described. These compounds are potent inhibitors of the 5-lipoxygenase from RBL-1 cells and also inhibit bovine seminal vesicle cyclooxygenase. Structure-activity relationships for these two enzymes are different, implying specific enzyme inhibition rather than a nonspecific antioxidant effect. 2-(Aryl-methyl)-1-naphthols are among the most potent 5-lipoxygenase inhibitors reported (IC50 values generally 0.01-0.2 microM) and show excellent antiinflammatory potency in the mouse arachidonic acid ear edema model. To study the effects of structure on in vitro and in vivo activity, four general features of the molecules were varied: the 2-substituent, the 1-hydroxyl group, substitution on the naphthalene rings, and the 1,2-disubstituted naphthalene unit itself. 2-Benzyl-1-naphthol (5a, DuP 654) shows a very attractive profile of topical antiinflammatory activity and is currently in clinical trials as a topically applied antipsoriatic agent.
本文描述了一系列在2-位带有碳取代基的1-萘酚的合成、生物学评价及构效关系。这些化合物是RBL-1细胞中5-脂氧合酶的强效抑制剂，同时也抑制牛精囊环氧化酶。这两种酶的构效关系不同，表明是特异性酶抑制而非非特异性抗氧化作用。2-(芳基甲基)-1-萘酚是已报道的最有效的5-脂氧合酶抑制剂之一（IC50值通常为0.01 - 0.2 microM），并且在小鼠花生四烯酸耳水肿模型中显示出优异的抗炎效力。为了研究结构对体外和体内活性的影响，对分子的四个一般特征进行了改变：2-取代基、1-羟基、萘环上的取代以及1,2-二取代萘单元本身。2-苄基-1-萘酚（5a，DuP 654）显示出非常有吸引力的局部抗炎活性，目前作为局部应用的抗银屑病药物正在进行临床试验。
