A rational approach to the design and synthesis of a new bradykinin B1 receptor antagonist

We have previously synthesized a potent and selective B-1 bradykinin receptor antagonist, JMV1645 (H-Lys-Arg-Pro-Hyp-Gly-Igl-Ser-D-BT-OH), containing a dipeptide mimetic ((3S)-amino-5-carbonylmethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (D-BT) moiety) at the C-terminal. Analogues of this potent B1 bradykinin receptor antagonist in which the central Pro(2)-Hyp(3)-Gly(4)-Igl(5) tetrapeptide has been replaced by constrained N-1-substituted-1,3,8-triazaspirol[4.5]decan-4-one ring system were synthesized. Among these analogues, compound JMV1640 (1) was found to have an affinity of 24.10 +/- 9.48 nM for the human cloned B-1 receptor. It antagonized the [des-Arg(10)]-kallidin-induced contraction of the human umbilical vein (pA(2) = 6.1 +/- 0.1). Compound 1 was devoid of agonist activity at the kinin B-1 receptor. Moreover, it did not bind to the human cloned B-2 receptor. Therefore, JMV1640 constitutes a lead compound for the rational search of nonpeptide B-1 receptor analogues based on the BK sequence.