N- Carboxylic Acids, Hydroxamic Acids, Tetrazoles, and Sulfonyl Carboxamides. Potent Orally Active Leukotriene D4 Antagonists of Novel Structure

Article abstract of DOI:10.1021/jm00163a039

Four series of N-<(arylmethoxy)phenyl> compounds were prepared as leukotriene D₄ (LTD₄) antagonists.In the hydroxamic acid series, methyl 3-(2-quinolinylmethoxy)benzeneacetohydroxamate (Wy-48,422, 20) was the most potent inhibitor of LTD₄-induced bronchoconstriction with an oral ED₅₀ of 7.9 mg/kg.Compound 20 was also orally inhibited ovalbumin-induced bronchoconstriction in the guinea pig with an ED₅₀ of 3.6 mg/kg.In vitro, against LTD₄-induced contraction of isolated guinea pig trachea pretreated with indomethacin and 1-cysteine, 20 produced a pK_B value of 6.08.In the sulfonyl carboxamide series, N-<(-4-methylphenyl)sulfonyl>-3-(2-quinolinylmethoxy)-benzamide (Wy-49,353, 30) was the most potent antagonist.Compound 30 orally inhibited both LTD4- and ovalbumin-induced bronchoconstriction with ED₅₀s of 0.4 and 20.2 mg/kg, respectively.In vitro, against LTD₄-induced contraction of isolated guinea pig trachea, 30 produced a pK_B value of 7.78.In the carboxylic acid series, which served as intermediates for the above two series, 3-(2-quinolinylmethoxy)benzeneacetic acid (Wy-46,016, 5) was the most potent inhibitor of LTD₄-induced bronchoconstriction (99percent at 25 mg/kg, intraduodenally); however, the pK_B for this compound was disappointing (5.79).In the tetrazole series, the most potent inhibitor was 2-<<3-(1H-tetrazol-5-ylmethyl)phenoxy>methyl>quinoline (Wy-49,451, 41).The respective inhibitory ED₅₀s were 3.0 mg/kg versus LTD₄ and 17.5 mg/kg versus ovalbumin.In the isolated guinea pig trachea, 41 produced a pK_B value of 6.70.