Synthesis and characterization of bradykinin B-2 receptor agonists containing constrained dipeptide mimics

We have previously shown that substitution of the D-Tic-Oic dipeptide by a (3S)-[amino]-5(carbonylmethyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (D- BT) moiety in the bradykinin B-2 receptor antagonist HOE 140 resulted in a full potent and selective bradykinin B-2 receptor agonist (H-DArg-Arg-Pro-H yp-Gly-Thi-Ser-D-BT-Arg-OH, JMV1116) exhibiting a high affinity for the hum an receptor (K-i 0.7 nM). In the present study, we have investigated the ef fects of replacement of the D-Tic-Oic moiety by various constrained dipepti de mimetics. The resulting compounds were tested for their binding affinity toward the cloned human B-2 receptor and for their functional interaction with the bradykinin-induced contraction of isolated human umbilical vein. S ubsequently, we have designed novel bradykinin B-2 receptor agonists which are likely to be resistant to enzymatic cleavage by endopeptidases and whic h might represent interesting new pharmacological tools. In an attempt to i ncrease the potency of compound JMV1116, both its N-terminal part and the D -BT moiety were modified. Substitution of the D-arginine residue by a L-lys ine residue led to a 10-fold more potent bradykinin B-2 ligand [compound 22 (JMV1465) (K-i 0.07 nM)], retaining full agonist activity on human umbilic al vein. Substitution of the D-BT moiety by a (3S)-[amino]-5-(carbonylmethy l)-2,3-dihydro-8-methyl-1,5-benzothiazepin-4(5H)-one [D-BT(Me)] moiety led to compound 23 (JMV1609) which exhibited a higher agonist activity (pD(2) = 7.4) than JMV1116 (pD(2) = 6.8).