Characterization of FR173657, a novel nonpeptide B2 antagonist: in vitro and in vivo studies.

Bradykinin (BK) is involved in different pathophysiological conditions, including allergic and (or) inflammatory reactions. Thus, BK antagonists are considered as a potential drug in allergic and (or) inflammatory diseases. Orally active BK antagonist would be desirable for this purpose. Here, we describe the pharmacological characterization of FR173657 ((E)-3-(6-acetamido-3-pyridyl)-N-[N-[2,4-dichloro-3-[(2-methyl-8- quinolinyl)oxymethyl]phenyl]-N-methylaminocarbonylmethyl]acr ylamide) obtained from our screening for nonpeptide, orally active B2 antagonists. (i) FR173657 antagonized [3H]BK binding with IC50 values of 4.6 x 10(-10) and 8.6 x 10(-9) M in membrane preparations of guinea pig ileum and lung, respectively. FR173657 inhibited [3H]BK binding to A431, W138, and IMR90 cell lines of human origin with IC50 values of 2.0 x 10(-9), 2.3 x 10(-9), and 1.7 x 10(-9) M, respectively. FR173657 did not affect [3H]des-Arg10-kallidin (B1 ligand) binding onto IMR90 cells. (ii) FR173657 inhibited guinea pig ileum contractions by BK (6 x 10(-8) M) with an IC50 value of 6.1 x 10(-9) M. Acetylcholine- and histamine-induced contraction of guinea pig ileum was unaffected by FR173657. (iii) Oral administration of FR173657 dose-dependently inhibited BK (5 micrograms/kg) and dextran sulfate (activator of kinin-kallikrein cascade) induced bronchoconstriction with ED50 values of 0.075 and 0.057 mg/kg, respectively. In conclusion, FR173657 is a selective potent, orally active B2 receptor antagonist that can be used to investigate the role of BK in allergic and inflammatory diseases.