Synthesis and Biological Evaluation of Bradykinin B₁/B₂ and Selective B₁ Receptor Antagonists

Abstract

We recently described a potent bradykinin B(2) receptor agonist (JMV1116) obtained by replacing the D-Tic-Oic dipeptide moiety of HOE140 by a (3S)-amino-5-(carbonylmethyl)-2,3-dihydro-1, 5-benzothiazepin-4(5H)-one (D-BT) moiety. This compound inhibited the specific binding of [(3)H]BK on membranes of CHO cells expressing the human cloned B(2) receptor with nanomolar affinity and contracted both isolated rat uterus and human umbilical vein. These data demonstrated that D-BT could be a good mimic of the Pro-Phe dipeptide. In the present study we characterized B(1) receptor antagonists containing the D-BT moiety. We prepared an analogue of compound JMV1116 deleting the C-terminal arginine residue. The resulting compound (1) had an affinity of 83 nM for the human cloned B(1) receptor. The most remarkable property of 1 is its ability to bind also the B(2) receptor with an affinity of 4.4 nM despite the absence of the C-terminal arginine residue. Modifications at the N-terminal part of 1 associated with the substitution of the thienylalanine residue by alpha-(2-indanyl)glycine resulted in analogues selectively binding to the B(1) receptor with an affinity in the picomolar range.

Coronary Vasomotor Response to the Selective B1-Kinin-Receptor Agonist Des-Arg9-Bradykinin in Humans

“…20 Because of this initial observation, vasoactive responses to B 1 -receptor ligands have been studied both in arteries and in veins, in a variety of species. 3,14,18,21 Vascular reactivity to the B 1 -receptor is not usually constitutively present, but is generally acquired after an inflammatory insult. 5,19,22,23 Interestingly, up-regulation of B 1 -receptors was involved in the regulation of the coronary circulation in rat and rabbit models of endotoxemia.…”

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

“…We recently described a series of B 2 receptor agonists in which the dipeptide Pro-Phe of BK or d -Tic-Oic of HOE140 was replaced by a benzothiazepinone (D-BT) moiety. , We also reported the synthesis of B 1 receptor antagonists based on the substitution of the dipeptide d -Igl-Oic of the potent B 1 receptor antagonist B9858 (H-Lys-Lys-Arg-Pro-Hyp-Gly-Igl-Ser- d -Igl-Oic-OH) 20 by a benzothiazepinone (D-BT) moiety. , Among the most potent compounds, JMV1645 (H-Lys-Arg-Pro-Hyp-Gly-Igl-Ser-D-BT-OH) had a K i value of 0.023 ± 0.001 nM on the human cloned B 1 receptor and a p A 2 of 8 on the human umbilical vein. Therefore, we focused our efforts on the synthesis of constrained peptidomimetics in order to approach a rational design of nonpeptide compounds.…”

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.…”