Structural requirements of leukotriene antagonists

The structural characteristics of benzanilide derivatives having alkyl or alkoxyl side chains on the benzoyl benzene ring and tetrazolyl oxygen-heterocycles condensed with the anilide benzene ring as leukotriene antagonists were examined in comparison with those of leukotrienes. The three-dimensional arrangements of the conjugated benzamide moiety, tetrazole and benzopyranone or benzodioxane ring, similar to those of the triene moiety, peptide carboxylic acid and cysteine residue of leukotrienes, respectively, were very important for the anti-leukotriene activity. Effective lengths of alkyl or alkoxyl chains in dynamic conformational equilibria were estimated by taking all possible conformations of these flexible chains into consideration. The effective lengths and conformations which are similar to those of the ω-chain of leukotrienes were required for the maximal antagonist activity, other things being equal. The terminal aliphatic carboxylic acid of leukotrienes was suggested to be essential for the agonistic activity.