Wy-48,252 (1,1,1-trifluoro-N-[3-(2-quinolinylmethoxy)phenyl]methane sulfonamide), an orally active leukotriene antagonist: effects on arachidonic acid metabolism in various inflammatory cells

Abstract The LTD 4 antagonist, Wy-48,252 (1,1,1-trifluoro-N-[3-(2-quinolinylmethoxy)phenyl]methanesulfonamide), was assessed for its ability to modulate arachidonic acid metabolism in several inflammatory cells. In A23187-stimulated rat neutrophils. Wy-48,252 effectively inhibited the conversion of exogenous [ 14 C]arachidonic acid to radiolabeled 5-hydroxyeicosatetraenoic acid (5-HETE) and thrombaxane B 2 (TxB 2 ) (IC 50 = 2 and 9.1 μ M, respectively). Synthesis of immunoreactive leukotriene B 4 (LTB 4 ) (IC 50 = 4.6 μM ) and TxB 2 (IC 50 = 3.3 μ M) from endogenous substrate by these cells in the absence of [ 14 C]arachidonic acid was similarly reduced. Wy-48,252 also reduced leukotriene C 4 (LTC 4 ) and PGE 2 synthesis by zymosan-activated mouse peritonel macrophages (IC 50 = 4.4 and 4.3 μ M, respectively). 5-Lipoxygenase (5-LO) catalyzed reactions in human neutrophils, lung mast cells and basophils activated by various stimuli were dose dependently inhibited by Wy-48,252 while PGD 2 synthesis by lung mast cells was inhibited at 100 μM. By contrast, 12-LO, 15-LO, phosphodiesterase activity and histamine release from mast cells and basophils were unaffected by Wy-48,252. These data suggested that the LTD 4 antagonist, Wyy-48,252, also inhibited the synthesis of eicosanoids, a feature that may contribute to its pharmacological actions in vivo.