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J Med Chem. 2018 Mar 22;61(6):2266-2277. doi: 10.1021/acs.jmedchem.7b01353. Epub 2018 Feb 26.

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

Author information

1
Département de Pharmacologie-Physiologie, Faculté de Médecine et des Sciences de la Santé , Université de Sherbrooke , Sherbrooke J1H 5N4 , Québec , Canada.
2
Institut de Pharmacologie de Sherbrooke , Sherbrooke J1H 5N4 , Québec Canada.
3
Département de Médecine, Faculté de Médecine et des Sciences de la Santé , Université de Sherbrooke , Sherbrooke J1H 5N4 , Québec , Canada.
4
IPS Thérapeutique Inc. , Sherbrooke J1G 5J6 , Québec , Canada.

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.

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