Effect of a novel leukotriene D4 antagonist with 5-lipoxygenase and cyclooxygenase inhibitory activity, Wy-45,911, on leukotriene-D4-and antigen-induced bronchoconstriction in the guinea pig.
Wy-45,911 (4-[hydroxy-[3-(2-quinolinylmethoxy)phenyl] amino]-4-oxabutanoic acid, methyl ester) was found to inhibit competitively leukotriene D4 (LTD4)-induced contractions of the isolated guinea pig trachea but not those of leukotriene C4 (LTC4), even in the presence of a gamma-glutamyltranspeptidase inhibitor, reduced glutathione (GSH). Tracheal contractions induced by histamine or pilocarpine were also not significantly altered by Wy-45,911. The drug inhibited the tracheal contractions induced by antigen, even in the presence of GSH. This latter effect resulted from inhibition of 5-lipoxygenase (5-LO), as the synthesis of 5-LO products by rat polymorphonuclear leukocytes and by mouse macrophages was markedly reduced by Wy-45,911. The drug inhibited both LTD4-induced and antigen-induced bronchoconstriction when injected intraduodenally or intragastrically into intact guinea pigs though it was more potent against LTD4-induced bronchoconstriction. We conclude that Wy-45,911 is a novel, orally active LTD4 antagonist in the guinea pig, with some 5-LO inhibitory activity.
Chang
J
J
Wyeth Laboratories, Inc., Philadelphia, Pa.
Musser
J H
JH
Hand
J M
JM
D000818:Animals; D000941:Antigens / Q000276:immunology*; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D001249:Asthma / Q000139:chemically induced / Q000276:immunology*; D016861:Cyclooxygenase Inhibitors; D006168:Guinea Pigs; D016859:Lipoxygenase Inhibitors; D008264:Macrophages / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D010529:Peritoneal Cavity / Q000166:cytology; D011804:Quinolines / Q000494:pharmacology*; D018077:Receptors, Leukotriene; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D013189:SRS-A / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000096:biosynthesis; D014132:Trachea / Q000187:drug effects / Q000502:physiology
D000941:Antigens; D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D011804:Quinolines; D018077:Receptors, Leukotriene; D011982:Receptors, Prostaglandin; D013189:SRS-A; C053879:Wy 45911; D016718:Arachidonic Acid; D013929:Thromboxane B2