Wy-48,252 (1,1,1-trifluoro-N-[3-(2-quinolinylmethoxy)phenyl]membrane sulfonamide), an orally active leukotriene antagonist: effects on arachidonic acid metabolism in various inflammatory cells.
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 thromboxane B2 (TxB2) (IC50 = 2 and 9.1 microM, respectively). Synthesis of immunoreactive leukotriene B4 (LTB4) (IC50 = 4.6 microM) and TxB2 (IC50 = 3.3 microM) 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 peritoneal macrophages (IC50 = 4.4 and 4.3 microM, 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 microM. 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, Wy-48,252, also inhibited the synthesis of eicosanoids, a feature that may contribute to its pharmacological actions in vivo.
Chang
J
J
Wyeth-Ayerst Research, Division of Experimental Therapeutics, Philadelphia, PA 19101.
Borgeat
P
P
Schleimer
R P
RP
Musser
J H
JH
Marshall
L A
LA
Hand
J M
JM
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D002417:Cattle; D004537:Eicosanoic Acids / Q000096:biosynthesis; D005260:Female; D006636:Histamine Release / Q000187:drug effects; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis; D006912:Hydroxyquinolines / Q000494:pharmacology*; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D051381:Rats; D011919:Rats, Inbred Strains; D013189:SRS-A / Q000037:antagonists & inhibitors*
D001095:Arachidonic Acids; D004537:Eicosanoic Acids; D006893:Hydroxyeicosatetraenoic Acids; D006912:Hydroxyquinolines; D013189:SRS-A; C056398:Wy 48252; D016718:Arachidonic Acid