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A Systematic Exploration of Macrocyclization in Apelin-13: Impact on Binding, Signaling, Stability, and Cardiovascular Effects
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-02-20 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01353
Kien Trân 1, 2 , Alexandre Murza 1, 2 , Xavier Sainsily 1, 2 , David Coquerel 2, 3 , Jérôme Côté 1, 2 , Karine Belleville 1, 2 , Lounès Haroune 1, 2 , Jean-Michel Longpré 1, 2 , Robert Dumaine 1, 2 , Dany Salvail 4 , Olivier Lesur 2, 3 , Mannix Auger-Messier 3 , Philippe Sarret 1, 2 , Éric Marsault 1, 2
Affiliation  

The apelin receptor generates increasing interest as a potential target across several cardiovascular indications. However, the short half-life of its cognate ligands, the apelin peptides, is a limiting factor for pharmacological use. In this study, we systematically explored each position of apelin-13 to find the best position to cyclize the peptide, with the goal to improve its stability while optimizing its binding affinity and signaling profile. Macrocyclic analogues showed a remarkably higher stability in rat plasma (half-life >3 h versus 24 min for Pyr-apelin-13), accompanied by improved affinity (analogue 15, Ki 0.15 nM and t1/2 6.8 h). Several compounds displayed higher inotropic effects ex vivo in the Langendorff isolated heart model in rats (analogues 13 and 15, maximum response at 0.003 nM versus 0.03 nM of apelin-13). In conclusion, this study provides stable and active compounds to better characterize the pharmacology of the apelinergic system.

中文翻译:

Apelin-13中大环化的系统探索:对结合,信号传导,稳定性和心血管效应的影响

作为多种心血管适应症的潜在靶标,apelin受体引起了越来越多的关注。然而,其同源配体,阿佩林肽的半衰期短,是药理学应用的限制因素。在这项研究中,我们系统地探索了apelin-13的每个位置,以找到使肽环化的最佳位置,目的是在优化其结合亲和力和信号传导特性的同时提高其稳定性。大环类似物在大鼠血浆中显示出显着更高的稳定性(半衰期> 3小时,而Pyr-apelin-13则为24分钟),并具有改善的亲和力(类似物15K i 0.15 nM和t 1/26.8小时)。几种化合物在大鼠Langendorff离体心脏模型中表现出更高的正性肌力作用(类似物1315,最大反应为0.003 nM,而apelin-13为0.03 nM)。总而言之,这项研究提供了稳定和活性的化合物,以更好地表征阿贝林能系统的药理学。
更新日期:2018-02-20
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