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

  • J Med Chem. 2018 Mar 22;61(6):2266-2277. doi: 10.1021/acs.jmedchem.7b01353.
Kien Trân  1  2 ,  Alexandre Murza  1  2 ,  Xavier Sainsily  1  2 ,  David Coquerel  3  2 ,  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  3  2 ,  Mannix Auger-Messier  3 ,  Philippe Sarret  1  2 ,  Éric Marsault  1  2
Affiliations
  • 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.
PMID: 29461833 DOI: 10.1021/acs.jmedchem.7b01353
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.