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

作者：Tran Kien; Murza Alexandre; Sainsily Xavier; Coquerel David; Cote Jerome; Belleville Karine; Haroune Lounes; Longpre Jean Michel; Dumaine Robert; Salvail Dany; Lesur Olivier; Auger Messier Mannix; Sarret Philippe; Marsault Eric^*

来源：Journal of Medicinal Chemistry, 2018, 61(6): 2266-2277.

DOI：10.1021/acs.jmedchem.7b01353

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.

• 出版日期2018-3-22