| Literature DB >> 29461833 |
Kien Trân1,2, Alexandre Murza1,2, Xavier Sainsily1,2, David Coquerel3,2, Jérôme Côté1,2, Karine Belleville1,2, Lounès Haroune1,2, Jean-Michel Longpré1,2, Robert Dumaine1,2, Dany Salvail4, Olivier Lesur3,2, Mannix Auger-Messier3, Philippe Sarret1,2, Éric Marsault1,2.
Abstract
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.Entities:
Mesh：
Substances：
Year: 2018 PMID： 29461833 DOI： 10.1021/acs.jmedchem.7b01353
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446