Goto S, Guo Z, Futatsuishi Y, Hori H, Taira Z, Terada H
Faculty of Pharmaceutical Sciences, University of Tokushima, Japan.
J Med Chem. 1992 Jun 26;35(13):2440-5. doi: 10.1021/jm00091a011.
To determine the structural requirements of the benzamide derivatives reported by Nakai et al. (J. Med. Chem. 1988, 31, 84-91) for antileukotriene activity, we studied their conformational characteristics in comparison with those of leukotriene. By superimpositions of the conformations of antagonists on that of leukotriene, we found that the conformations of the conjugated benzamide moiety, tetrazole ring, and benzopyran or benzodioxan ring of the antagonists correspond to the triene moiety, peptide carboxylic acid residue, and cysteine residue of leukotriene, respectively, but that no moiety of the antagonists corresponds to the terminal aliphatic carboxylic acid moiety of leukotriene. Furthermore, the stable conformations of alkyl and alkoxy groups of the antagonists were quite different from that of the omega-chain of leukotriene. However, conformational analyses taking all the possible rotations of these flexible chains into consideration showed that antagonists in which these flexible chains can most feasibly adopt the same lengths as those of the omega-chain exhibit potent antagonist activity. From these results, we deduced the structural features of benzamide derivatives necessary for potent antileukotriene activity.
为了确定中井等人（《药物化学杂志》，1988年，第31卷，84 - 91页）报道的苯甲酰胺衍生物的抗白三烯活性的结构要求，我们研究了它们与白三烯相比的构象特征。通过将拮抗剂的构象与白三烯的构象进行叠加，我们发现拮抗剂的共轭苯甲酰胺部分、四唑环以及苯并吡喃或苯并二恶烷环的构象分别对应于白三烯的三烯部分、肽羧酸残基和半胱氨酸残基，但拮抗剂没有任何部分对应于白三烯的末端脂肪族羧酸部分。此外，拮抗剂的烷基和烷氧基的稳定构象与白三烯的ω链的构象有很大不同。然而，考虑到这些柔性链的所有可能旋转的构象分析表明，这些柔性链最有可能采用与ω链相同长度的拮抗剂表现出强大的拮抗活性。从这些结果中，我们推断出了具有强大抗白三烯活性的苯甲酰胺衍生物的结构特征。
