Inhibitory effect of the newly synthesized pyridazinone derivative NZ-107 on bronchoconstriction induced by slow reacting substance of anaphylaxis in the guinea pig.

We have investigated the effect of a newly synthesized compound NZ-107, 4-bromo-5-(3-ethoxy-4-methoxybenzylamino)-3(2H)-pyridazinone, on bronchoconstriction induced by slow reacting substance of anaphylaxis (SRS-A) in the guinea pig. Orally administered NZ-107 (10 mg/kg, 2 hr) inhibited antigen-induced SRS-A-mediated bronchoconstriction in sensitized guinea pigs. NZ-107 (2 mg/kg, i.v., 1 min) prevented the antigen-induced response about as well as the SRS-A antagonist FPL-55712 and rapidly reversed it. This rapid reversal by NZ-107 but not FPL-55712 also appeared with the leukotriene (LT) D4-induced contraction of the isolated trachea. NZ-107 more selectively inhibited the LTD4 response than those of histamine, acetylcholine and KCl. Compared to FPL-55712, NZ-107 was one-fifteenth less potent in inhibiting the LTD4 response, but two-fold more potent in inhibiting the LTC4 response. NZ-107 inhibited the LTD4 response of the trachea 10-fold more potently than that of the ileum (-log IC50: trachea 5.61, ileum 4.56). The combination of NZ-107 (1 microM) with the beta-agonist isoproterenol had no synergistic effect on the LTD4 response, but those of theophylline and papaverine had large effects. From these results, NZ-107 is a selective inhibitor of the SRS-A response and may be useful in the therapy of bronchial asthma and other diseases in which the LTs are thought to be involved.