Pharmacological characterization of a novel, orally active, nonpeptide bradykinin B 2 receptor antagonist, FR167344

Abstract

To investigate the pathophysiological role of bradykinin and to develop a drug for inflammatory diseases, we discovered an orally active, nonpeptide bradykinin B 2 receptor antagonist, FR167344, N-[ N-[3-[(3-bromo-2-methylimidazo[1,2-a]pyridin-8-yl)oxymethyl]-2,4-dichlorophenyl]- N-methylaminocarbonylmethyl]-4-(dimethylaminocarbonyl) cinnamylamide hydrochloride. This compound competitively displaced [ 3 H ]bradykinin binding to bradykinin B 2 receptors present in guinea pig ileum membrane with an IC 50 value of 6.6×10 −10 M. In isolated guinea pig ileum preparations, it also antagonized bradykinin-induced contraction with a pA 2 value of 9.3. In human lung fibroblast IMR-90 cells, FR167344 displaced [ 3 H ]bradykinin binding to human bradykinin B 2 receptors with an IC 50 value of 1.3×10 −8 M, but not [ 3 H ]des-Arg 10–kallidin binding to human bradykinin B 1 receptors. In vivo, oral administration of FR167344 inhibited bradykinin-induced bronchoconstriction in guinea pigs and the bradykinin-induced hypotensive response for 6 h in rats. These results show that FR167344 is a potent, selective, orally active and long acting bradykinin B 2 receptor antagonist.