Synthesis and Biological Evaluation of Bradykinin B<INF>1</INF>/B<INF>2</INF> and Selective B<INF>1</INF> Receptor Antagonists

We recently described a potent bradykinin B<INF>2</INF> receptor agonist (JMV1116) obtained by replacing the <SCP>d</SCP>-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 [³H]BK on membranes of CHO cells expressing the human cloned B<INF>2</INF> 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<INF>1</INF> receptor antagonists containing the D-BT moiety. We prepared an analogue of compound JMV1116 deleting the C-terminal arginine residue. The resulting compound (<BO>1</BO>) had an affinity of 83 nM for the human cloned B<INF>1</INF> receptor. The most remarkable property of <BO>1 </BO>is its ability to bind also the B<INF>2</INF> receptor with an affinity of 4.4 nM despite the absence of the C-terminal arginine residue. Modifications at the N-terminal part of <BO>1</BO> associated with the substitution of the thienylalanine residue by α-(2-indanyl)glycine resulted in analogues selectively binding to the B<INF>1</INF> receptor with an affinity in the picomolar range.