A Rational Approach to the Design and Synthesis of a New Bradykinin B1 Receptor Antagonist

We have previously synthesized a potent and selective B1 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 Analogues of this potent B1 bradykinin receptor antagonist in which the central Pro2-Hyp3-Gly4-Igl5 tetrapeptide has been replaced by constrained N-1-substituted-1,3,8-triazaspiro[4.5]decan-4-one ring system were synthesized.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 B1 receptor. It antagonized the [des-Arg10]-kallidin-induced contraction of the human umbilical vein (pA 2 = 6.1 ± 0.1). Compound 1 was devoid of agonist activity at the kinin B1 receptor. Moreover, it did not bind to the human cloned B2 receptor. Therefore, JMV1640 constitutes a lead compound for the rational search of nonpeptide B1 receptor analogues based on the BK sequence.