Synthesis and Biological Evaluation of Bradykinin B1/B2 and Selective B1 Receptor Antagonists

We recently described a potent bradykinin B 2 receptor agonist (JMV1116) obtained by replacing the D-Tic-Oic dipeptide moiety of HOE140 by a (3S)-amino-5-(carbonylmethyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (D-BT) moiety. This compound inhibited the specific binding of [ 3 H]BK on membranes of CHO cells expressing the human cloned B 2 receptor with nanomolar affinity and contracted both isolated rat uterus and human umbilical vein. These data demonstrated that D-BT could be a good mimic of the Pro-Phe dipeptide. In the present study we characterized B 1 receptor antagonists containing the D-BT moiety. We prepared an analogue of compound JMV1116 deleting the C-terminal arginine residue. The resulting compound (1) had an affinity of 83 nM for the human cloned B 1 receptor. The most remarkable property of 1 is its ability to bind also the B 2 receptor with an affinity of 4.4 nM despite the absence of the C-terminal arginine residue. Modifications at the N-terminal part of 1 associated with the substitution of the thienylalanine residue by α-(2-indanyl)glycine resulted in analogues selectively binding to the B 1 receptor with an affinity in the picomolar range.