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

<jats:p> <jats:list list-type="explicit-label"> <jats:list-item><jats:p>An orally active, nonpeptide bradykinin (BK) B<jats:sub>2</jats:sub> 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.</jats:p></jats:list-item> <jats:list-item><jats:p>This compound displaced [<jats:sup>3</jats:sup>H]‐BK binding to B<jats:sub>2</jats:sub> receptors present in guinea‐pig ileum membranes with an IC<jats:sub>50</jats:sub> of 5.6 × 10<jats:sup>−10</jats:sup> M and in rat uterus with an IC<jats:sub>50</jats:sub> of 1.5 × 10<jats:sup>−9</jats:sup> M. It did not inhibit different specific radio‐ligand binding to other receptor sites.</jats:p></jats:list-item> <jats:list-item><jats:p>In human lung fibroblast IMR‐90 cells, FR173657 displaced [<jats:sup>3</jats:sup>H]‐BK binding to B<jats:sub>2</jats:sub> receptors with an IC<jats:sub>50</jats:sub> of 2.9 × 10<jats:sup>−9</jats:sup> M and a <jats:italic>K</jats:italic><jats:sub>i</jats:sub> of 3.6 × 10<jats:sup>−10</jats:sup> M, but did not reduce [<jats:sup>3</jats:sup>H]‐des‐Arg<jats:sup>10</jats:sup>‐kallidin binding to B<jats:sub>1</jats:sub>, receptors.</jats:p></jats:list-item> <jats:list-item><jats:p>In guinea‐pig isolated preparations, FR173657 antagonized BK‐induced contractions with an IC<jats:sub>50</jats:sub> of 7.9 × 10<jats:sup>−9</jats:sup> M, but did not antagonize acetylcholine or histamine‐induced contractions even at a concentration of 10<jats:sup>−6</jats:sup> M. FR173657 caused parallel rightward shifts of the concentration‐response curves to BK at concentrations of 10<jats:sup>−9</jats:sup> M and 3.2 × 10<jats:sup>−9</jats:sup> 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<jats:sup>−8</jats:sup> M. Analysis of the data yield a pA<jats:sub>2</jats:sub> of 9.2 ± 0.2 (<jats:italic>n</jats:italic> = 5) and a slope of 1.5 ± 0.2 (<jats:italic>n</jats:italic> = 5).</jats:p></jats:list-item> <jats:list-item><jats:p><jats:italic>In vivo</jats:italic>, the oral administration of FR173657 inhibited BK‐induced bronchoconstriction dose‐dependently in guinea‐pigs with an ED<jats:sub>50</jats:sub> of 0.075 mg kg<jats:sup>−1</jats:sup>, but did not inhibit histamine‐induced bronchoconstriction even at 1 mg kg<jats:sup>−1</jats:sup>. FR173657 also inhibited carrageenin‐induced paw oedema with an ED<jats:sub>50</jats:sub> of 6.8 mg kg<jats:sup>−1</jats:sup> 2 h after the carrageenin injection in rats.</jats:p></jats:list-item> <jats:list-item><jats:p>These results show that FR173657 is a potent, selective, and orally active bradykinin B<jats:sub>2</jats:sub> receptor antagonist.</jats:p></jats:list-item> </jats:list> </jats:p>