A rational approach to the design and synthesis of a new bradykinin B(1) receptor antagonist.

P Bedos, M Amblard, G Subra, P Dodey, J M Luccarini, J L Paquet, D Pruneau, A Aumelas, J Martinez

Laboratoire des Aminoacides Peptides et Protéines, UMR5810-CNRS, Universités Montpellier I et II, Faculté de Pharmacie, 15 Av. C. Flahault, 34060 Montpellier Cédex, France.

Journal of medicinal chemistry 2000 Jun 15

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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of this potent B(1) bradykinin receptor antagonist in which the central Pro(2)-Hyp(3)-Gly(4)-Igl(5) tetrapeptide has been replaced by constrained N-1-substituted-1,3,8-triazaspiro¿4. 5decan-4-one ring system were synthesized.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.

Citation

P Bedos, M Amblard, G Subra, P Dodey, J M Luccarini, J L Paquet, D Pruneau, A Aumelas, J Martinez. A rational approach to the design and synthesis of a new bradykinin B(1) receptor antagonist. Journal of medicinal chemistry. 2000 Jun 15;43(12):2387-94