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

Joseph Chang*, Pierre Borgeat, Robert P. Schleimer, John H. Musser, Lisa A. Marshall, James M. Hand

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

The LTD4 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 [14C]arachidonic acid to radiolabeled 5-hydroxyeicosatetraenoic acid (5-HETE) and thrombaxane B2 (TxB2) (IC50 = 2 and 9.1 μM, respectively). Synthesis of immunoreactive leukotriene B4 (LTB4) (IC50 = 4.6 μM) and TxB2 (IC50 = 3.3 μM) from endogenous substrate by these cells in the absence of [14C]arachidonic acid was similarly reduced. Wy-48,252 also reduced leukotriene C4 (LTC4) and PGE2 synthesis by zymosan-activated mouse peritonel macrophages (IC50 = 4.4 and 4.3 μM, 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 PGD2 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 LTD4 antagonist, Wyy-48,252, also inhibited the synthesis of eicosanoids, a feature that may contribute to its pharmacological actions in vivo.

Original languageEnglish (US)
Pages (from-to)131-141
Number of pages11
JournalEuropean Journal of Pharmacology
Volume148
Issue number1
DOIs
StatePublished - Mar 22 1988

Keywords

  • 5-Lipoxygenase
  • Cyclooxygenase
  • LTD receptor
  • Leukocytes
  • Wy-48,252

ASJC Scopus subject areas

  • Pharmacology

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