QUANTITATIVE STRUCTURE-ACTIVITY-RELATIONSHIPS OF BENZAMIDE DERIVATIVES FOR ANTI-LEUKOTRIENE ACTIVITIES

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.