The identification of an orally active, nonpeptide bradykinin B2 receptor antagonist, FR173657

1 An orally active, nonpeptide bradykinin (BK) B2 receptor antagonist, FR173657 (E)-3-(6-acetamido-3-pyridyl)-N-[N-[2-4-dichloro-3-[(2-methyl-8-quinolinyl) oxymethyl]phenyl]-N-methylaminocarbonyl-methyl]acrylamide) has been identified. 2 This compound displaced [3H]-BK binding to B2 receptors present in guinea-pig ileum membranes with an IC50 of 5.6 × 10−10 M and in rat uterus with an IC50 of 1.5 × 10−9 M. It did not inhibit different specific radio-ligand binding to other receptor sites. 3 In human lung fibroblast IMR-90 cells, FR173657 displaced [3H]-BK binding to B2 receptors with an IC50 of 2.9 × 10−9 M and a Ki of 3.6 × 10−10 M, but did not reduce [3H]-des-Arg10-kallidin binding to B1, receptors. 4 In guinea-pig isolated preparations, FR173657 antagonized BK-induced contractions with an IC50 of 7.9 × 10−9 M, but did not antagonize acetylcholine or histamine-induced contractions even at a concentration of 10−6 M. FR173657 caused parallel rightward shifts of the concentration-response curves to BK at concentrations of 10−9 M and 3.2 × 10−9 M, and a little depression of the maximal response in addition to the parallel rightward shift of the concentration-response curve at a concentration of 10−8 M. Analysis of the data yield a pA2 of 9.2 ± 0.2 (n = 5) and a slope of 1.5 ± 0.2 (n = 5). 5 In vivo, the oral administration of FR173657 inhibited BK-induced bronchoconstriction dose-dependently in guinea-pigs with an ED50 of 0.075 mg kg−1, but did not inhibit histamine-induced bronchoconstriction even at 1 mg kg−1. FR173657 also inhibited carrageenin-induced paw oedema with an ED50 of 6.8 mg kg−1 2 h after the carrageenin injection in rats. 6 These results show that FR173657 is a potent, selective, and orally active bradykinin B2 receptor antagonist.