title: Development of Potent and Metabolically Stable APJ Ligands with High Therapeutic Potential.
abstract: The apelin ligand receptor system is an important target to develop treatment strategies for cardiovascular diseases. Although apelin exhibits strong inotropic effects, its pharmaceutical application is limited because no agonist with suitable properties is available. On the one hand, peptide ligands are too instable, and on the other hand, small-molecule agonists show only low potency. This study describes the development of apelin (APJ) receptor agonists with not only high activity but also metabolic stability. Several strategies including capping of termini, insertion of unnatural amino acids, cyclization, and lipidation were analyzed. Peptide activity was tested using a Ca2+-mobilization assay and the degradation of selected analogues was analyzed in rat plasma. The best results were obtained by N-terminal lipidation of a 13-mer apelin derivative. This analogue displayed a half-life of 29 h in rat plasma, compared with 0.025 h for the wild-type peptide. Furthermore, in vivo pharmacokinetics revealed a clearance of 0.049 L h-1kg-1and a half-life of 0.36 h. In summary, amino acid substitution and fatty acid modification resulted in a potent and 1000-fold more stable peptide that exhibits high pharmaceutical potential.
authors: Department of Medicinal Chemistry, Bayer Pharma AG, Aprather Weg 18 A, 42096, Wuppertal, Germany.
authors: Cathleen
authors: C
authors: Juhl
authors: Institute of Biochemistry, Leipzig University, Brüderstraße 34, 04103, Leipzig, Germany.
authors: Sylvia
authors: S
authors: Els-Heindl
authors: Institute of Biochemistry, Leipzig University, Brüderstraße 34, 04103, Leipzig, Germany.
authors: Ria
authors: R
authors: Schönauer
authors: Global External Innovation & Alliances, Bayer Pharma AG, Aprather Weg 18 A, 42096, Wuppertal, Germany.
authors: Gorden
authors: G
authors: Redlich
authors: Department of Pharmacokinetics and Metabolism, Bayer Pharma AG, Aprather Weg 18 A, 42096, Wuppertal, Germany.
authors: Erik
authors: E
authors: Haaf
authors: Lead Discovery Wuppertal, Bayer Pharma AG, Aprather Weg 18 A, 42096, Wuppertal, Germany.
authors: Frank
authors: F
authors: Wunder
authors: Department of Medicinal Chemistry, Bayer Pharma AG, Aprather Weg 18 A, 42096, Wuppertal, Germany.
authors: Bernd
authors: B
authors: Riedl
authors: Lead Discovery Wuppertal, Bayer Pharma AG, Aprather Weg 18 A, 42096, Wuppertal, Germany.
authors: Nils
authors: N
authors: Burkhardt
authors: Institute of Biochemistry, Leipzig University, Brüderstraße 34, 04103, Leipzig, Germany.
authors: Annette G
authors: AG
authors: Beck-Sickinger
authors: Department of Medicinal Chemistry, Bayer Pharma AG, Aprather Weg 18 A, 42096, Wuppertal, Germany.
authors: Donald
authors: http://orcid.org/0000-0001-6580-2520
authors: D
authors: Bierer
keywords: G protein-coupled receptors; apelin; lipidation; peptides; structure-activity relationships