A rational approach to the design and synthesis of a new bradykinin B(1) receptor antagonist
| Autor: | Gilles Subra, ‡ Jean-Michel Luccarini, Philippe Bedos, Jean Martinez, Pierre Dodey, Didier Pruneau, ‡ Jean-Luc Paquet, Muriel Amblard, and André Aumelas |
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| Rok vydání: | 2000 |
| Předmět: |
Agonist
Umbilical Veins Magnetic Resonance Spectroscopy medicine.drug_class Stereochemistry Thiazepines Bradykinin CHO Cells In Vitro Techniques Receptor Bradykinin B1 Transfection Muscle Smooth Vascular chemistry.chemical_compound Structure-Activity Relationship Cricetinae Drug Discovery medicine Animals Bradykinin receptor Receptor Bradykinin Receptor Antagonists Tetrapeptide Chemistry Antagonist Kinin Receptor antagonist Drug Design Molecular Medicine Oligopeptides Muscle Contraction |
| Zdroj: | Journal of medicinal chemistry. 43(12) |
| ISSN: | 0022-2623 |
| Popis: | 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of this potent B(1) bradykinin receptor antagonist in which the central Pro(2)-Hyp(3)-Gly(4)-Igl(5) tetrapeptide has been replaced by constrained N-1-substituted-1,3,8-triazaspiro?4. 5decan-4-one ring system were synthesized.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. |
| Databáze: | OpenAIRE |
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