Effects of NIP-502 on antigen-induced bronchial responses and allergic reactions in animal models

We examined the effect of a newly synthesized pyridazinone derivative, NIP-502 [4-chloro-5-(3-ethoxy)-4-phenoxybenzamine)-3(2H)-pyridazinone], on antigen-induced bronchial responses and allergic reactions in several animal models. NIP-502 (10 mg/kg, p.o.) inhibited the antigen-induced immediate asthmatic response in passively sensitized guinea pigs. The inhibitory effect was also observed in metyrapone (an inhibitor of 11 beta-hydroxylase)-pretreated guinea pigs. NIP-502 improved ovalbumin (OA)-induced airway hyperresponsiveness to acetylcholine and inhibited the OA-induced increase in the number of inflammatory leukocytes in the bronchoalveolar lavage fluid. These inhibitory effects on OA-induced responses were similar to those of prednisolone. NIP-502 also showed an inhibitory effect on the passive cutaneous anaphylactic reaction in rats but did not inhibit the reversed cutaneous anaphylactic reaction, reversed Arthus reaction or delayed type hypersensitivity reaction. On the other hand, prednisolone showed broad inhibitory effects except for the reversed cutaneous anaphylactic reaction. In the in vitro study, NIP-502 (30 microM) significantly inhibited Formyl-Met-Leu-Phe-induced superoxide anion production by the guinea pig alveolar macrophages. These results indicate that the inhibitory effects of NIP-502 on bronchial responses are similar to those of prednisolone, but this compound seemed to act more selectively on the respiratory tract than prednisolone. Because of its effectiveness against a variety of bronchial responses, NIP-502 may be useful in the treatment of bronchial asthma.