N- and N- Sulfonamides: Potent Orally Active Leukotriene D4 Antagonists of Novel Structurs

Article abstract of DOI:10.1021/jm00126a006

Two series of compounds, N-<(arylmethoxy)phenyl> sulfonamides and N-<(arylmethoxy)naphtyl> sulfonamides, were prepared as leukotriene D₄ (LTD₄) antagonists.In the phenyl series, N-<3-(2-quinolinylmethoxy)phenyl>-trifluoromethanesulfonamide (Wy-48,252, 16) was the most potent inhibitor of LTD₄-induced bronchoconstriction in the guinea pig.With an intragastric ID 50 of 0.1 mg/kg (2-h pretreatment), 16 was 300 times more potent than LY-171,883.Compound 16 also intragastrically inhibited ovalbumin-induced bronchoconstriction in the guinea pig with an ID 50 of 0.6mg/kg.In vitro against LTD₄-induced contraction of isolated guinea pig trachea pretreated with indomethacin and L-cysteine, 16 produced a pK_B value of 7.7.In the rat PMN assay 16 inhibited both 5-lipoxygenase and cyclooxygenase (IC 50's = 4.6 and 3.3 μM).In the naphthyl series, N-<7-(2-quinolinylmethoxy)-2-naphthyl>trifluoromethanesulfonamide (Wy-48,090, 47) in addition to potent LTD₄ antagonist activity (on isolated guinea pig trachea 47 had a pK_B value of 7.04) also had antiinflammatory activity (63percent inhibition at 50 mg/kg in the rat carrageenan paw edema assay and 34percent inhibition of TPA-induced inflammation at 1 mg/ear in the mouse ear edema model).Perhaps the antiinflammatory activity of 47 was due to its additional activity of inhibiting both 5-lipoxygenase and cyclooxygenase enzymes (IC 50's = 0.23 and 11.9 μM, respectively, in rat PMN).