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

Abstract

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of this potent B(1) bradykinin receptor antagonist in which the central Pro(2)-Hyp(3)-Gly(4)-Igl(5) tetrapeptide has been replaced by constrained N-1-substituted-1,3,8-triazaspiro¿4. 5decan-4-one ring system were synthesized.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

International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences

“…In the anesthetized dog representing a hemodynamic system with mixed B 1 and B 2 receptor responses (see below), B9858 is reported to be 20 times more potent than Lys- [Leu 8 ]des-Arg 9 -BK in antagonizing des-Arg 9 -BK-induced hypotension, and the antagonist effect lasts for more than 4 h (versus about 15 min for Lys- [Leu 8 ]desArg 9 -BK; Stewart et al, 1996). Numerous structural experiments have been conducted with peptide kinin antagonists, such as producing pseudopeptides that retain limited structural elements of the parent peptide (Chakravarty et al, 1995;Galoppini et al, 1999;Bedos et al, 2000), or the production of dimers of antagonists. An early implementation of the latter idea was deltibant (CP-0127), the homodimer of D ]BK coupled through the side chains of Cys 6 by the linker bis-succinimidohexane.…”

Synthesis of optically active 1,5-benzothiazepines

“…o-Fluoronitrobenzene ( Solid-phase synthesis of optically active 3-amino-2,3-dihydro-1,5-benzothiazepin-4(5H)-ones, using cysteine derivatives as building blocks, has also been described in the literature. 29 Amblard et al [30][31][32][33] Its effectiveness stimulated the efforts to develop various synthetic protocols for its preparation. These efforts were further supported by the fact that nowadays only optically pure active ingredients are allowed to use for the production and sale of medicines.…”

Design and Synthesis of Protein Superfamily-Targeted Chemical Libraries for Lead Identification and Optimization

“…A solid phase route to bradykinin B1 receptor antagonists has been disclosed by Bedos [72]. A ten-step synthesis was developed, leading to the discovery of JMV1640, (25), a potent, small molecule antagonist, lacking activity against the B2 receptor.…”