Effect of FK3657, a non-peptide bradykinin B2 receptor antagonist, on allergic airway disease models

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.