INHIBITORY EFFECT OF DS-4574 ON LEUKOTRIENE-INDUCED OR ANTIGEN-INDUCED BRONCHOCONSTRICTION IN GUINEA-PIGS

We studied the leukotriene (LT) antagonistic activity of DS-4574 in vivo an the inhibitory effect of this compound on antigen-induced bronchoconstriction in actively sensitized guinea pigs. Bronchoconstriction induced by LTD4 was inhibited by intravenous and oral treatment with DS-4574 in a dose-dependent manner. Orally administered DS-4574 was also able to inhibit the bronchoconstriction mediated by intravenous administration of LTC4 and E4 and that by endogenous LTs. The inhibitory effect of DS-4574 showed similar potency to those of FPL-55712 and LY171883. In contrast, histamine-, acetylcholine- or 5-hydroxytryptamine-induced bronchoconstriction was not significantly affected by DS-4574. Moreover, DS-4574 given orally or intravenously inhibited antigen-induced bronchoconstriction in actively sensitized guinea pigs and this compound prevented antigen-induced mediator release from actively sensitized guinea-pig lung fragments. The anti-asthmatic effect of this compound appears to be associated with LT antagonism and inhibition of the release of chemical mediators. This study therefore shows DS-4574 to have orally effective LT antagonistic and anti-asthmatic activities. This compound may prove useful in the treatment of bronchial asthma.