Discovery of orally active nonpeptide bradykinin B-2 receptor antagonists

Orally active nonpeptide bradykinin (BK) B-2 receptor antagonists have been discovered by using directed random screening and chemical modification. T hese compounds displaced [H-3]BK binding to B-2 receptors in guinea-pig ile um membranes, rat uterus membranes and human lung fibroblasts with nanomola r IC(50)s. They did not inhibit different specific radio-ligand bindings to other receptor sites including B-1 receptors. In isolated guinea-pig ileum preparations, these compounds had no agonistic effect on smooth muscle con traction at 10(-6) M, and caused parallel rightward shifts of the concentra tion-response curves to BK on contraction with higher pA(2) values. They al so blocked human B-2 receptor-mediated phosphatidylinositol hydrolysis with out agonistic effect. In vivo, the oral administrations of these antagonist s potently inhibited BK-induced bronchoconstriction in guinea-pigs. They al so reduced carrageenin-induced paw edema and caerulein-induced pancreatitis in rats. Moreover, these compounds alleviated kaolin-induced pain in mice by oral administration. These results show that our compounds are potent, s elective, and orally active BK Bt receptor antagonists and that they may ha ve therapeutic potential against inflammatory diseases and pain. (C) 1999 E lsevier Science B.V. All rights reserved.