Effect of FK3657, a non-peptide bradykinin B 2 receptor antagonist, on allergic airway disease models

Abstract

Bradykinin has been suggested to be involved in allergic diseases. In this study, we tested the effect of FK3657 (( E)-3-(6-acetamido-3-pyridyl)- N-[ N-[2,4-dichloro-3-[(2-methyl-8-quinolinyl)-oxymethyl]phenyl]- N-methylaminocarbonylmethyl]acrylamide), an orally active non-peptide bradykinin B 2 receptor antagonist, on allergic airway disease models in guinea pigs. FK3657 given orally inhibited bradykinin-induced or dextran sulfate (an activator of kinin–kallikrein cascade)-induced bronchoconstriction and plasma extravasation in the lower airways (trachea and main bronchi) and nasal mucosa of guinea pigs with ED 50 of 0.04–0.23 mg/kg. In the antigen-induced dual asthmatic response model of guinea pigs, FK3657 significantly attenuated the late phase asthmatic response, but not the immediate asthmatic response. FK3657 also significantly inhibited the 2,4-tolylene diisocyanate (TDI)-induced plasma extravasation in nasal mucosa of TDI-sensitized guinea pigs. These results suggest that oral FK3657 may be useful for asthma or allergic rhinitis as a therapeutic drug.