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...

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Published inJournal of medicinal chemistry Vol. 43; no. 12; pp. 2387 - 2394
Main Authors Bedos, Philippe, Amblard, Muriel, Subra, Gilles, Dodey, Pierre, Luccarini, Jean-Michel, Paquet, Jean-Luc, Pruneau, Didier, Aumelas, André, Martinez, Jean
Format Journal Article
LanguageEnglish
Published Washington, DC American Chemical Society 15.06.2000
Subjects
Biological and medical sciences
Medical sciences
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems
Pharmacology. Drug treatments
Molecular rigidity
Sulfur nitrogen heterocycle
Peptides
Nitrogen heterocycle
Peptidomimetic compound
Lactam
Steric hindrance
In vitro
Spiran
Structure activity relation
Bradykinin
Bicyclic compound
Dipeptides
Peptidergic receptor
Aromatic compound
Peptide synthesis
Antagonist
Solid phase
Chemical synthesis
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Summary: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 Analogues of this potent B1 bradykinin receptor antagonist in which the central Pro2-Hyp3-Gly4-Igl5 tetrapeptide has been replaced by constrained N-1-substituted-1,3,8-triazaspiro[4.5]decan-4-one ring system were synthesized.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.
Bibliography:ark:/67375/TPS-6CFZFS7H-6
istex:29D15B56614D4E434836F96C19B74A3A8A9AC7BF
ISSN:0022-2623
1520-4804
DOI:10.1021/jm990962k