A Systematic Exploration of Macrocyclization in Apelin-13: Impact on Binding, Signaling, Stability, and Cardiovascular Effects,Journal of Medicinal Chemistry

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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, K_i 0.15 nM and t_1/2 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15，K _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13和15，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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