(Phenylmethoxy)phenyl Derivatives of Ω-Oxo- and Ω-Tetrazolylalkanoic Acids and Related Tetrazoles. Synthesis and Evaluation as Leukotriene D4 Receptor Antagonists

Article abstract of DOI:10.1021/jm00113a014

Two series of (phenylmethoxy)phenyl compounds derived from the structure of LY163443 were synthesized and evaluated as leukotriene D₄ receptor antagonists.In the Ω-<(phenylmethoxy)phenyl>-Ω-oxoalkanoic acid series, 5-<4-<(4-acetyl-2-ethyl-3-hydroxyphenyl)methoxy>phenyl>-3,3-dimethyl-5-oxopentanoic acid (8) was the most potent antagonist of LTD₄-induced contractions of guinea pig ileum (pK_B of 7.60) and LTD₄ pressor response in pithed rats (ED50 of 1.4 mg/kg iv).Replacing the carboxylic acid function with 5-tetrazole gave slightly more potent compounds.Inthe Ω-<5-<<(phenylmethoxy)phenyl>alkyl>tetrazolyl>alkanoic acid series, replacing the carboxylic acid with 5-tetrazole gave compounds that were equally effective in the guinea pig ileum but more potent in vivo against the LTD₄ pressor response in rat.The pK_B value in the guinea pig ileum for 1-<2-hydroxy-3-propyl-4-<<4-<<2-<3-(1H-tetrazol-5-yl)propyl>-2H-tetrazol-5-yl>methyl>phenoxy>methyl>phenyl>ethanone (25) was 7.87 and the ED50 for antagonism of the LTD₄ pressor response was 4.0 mg/kg iv.The sodium salts of 8 (9) and 25(26) given by the iv route of administration antagonized LTD₄-induced cardiovascular alterations in anesthetized rat and LTD₄-induced bronchoconstriction in guinea pig in a dose-dependent manner.Oral activity was also demonstrated against the LTD₄-induced bronchoconstriction in guinea pig.