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On the importance of metabolic stability to achieve high oral exposures for cyclic peptides

Vorherr, Thomas, Lewis, Ian, Wille, Roman Mariano, Lochmann, Thomas, Berghausen, Joerg, Huth, Felix, Schroer, Kirsten, Blanz, Joachim, Aichholz, Reiner and Schaefer, Michael (2020) On the importance of metabolic stability to achieve high oral exposures for cyclic peptides. American Journal of Medicinal Chemistry.


Following up on a previous publication in which we reported a high liver first pass effect in rats for the cyclic peptide (1) [Ala-Leu-NMe-D-Leu-NMe-Leu-Leu-D-Pro], we decided to investigate the type of metabolites formed and to suggest solutions to this problem. As a result of a bile duct cannulation study in rats and subsequent derivatization of this peptide by an isolated Cyp-enzyme, several hydroxylated variants were identified. Cyclopropyl-Ala (Cpa) residues as surrogates for Leu alleviated metabolism at these particular side chains. Significant progress was achieved, when in addition the D-Pro residue was exchanged by 4,4 difluoro-D-Pro (DiF-D-Pro). Albeit the Ala was kept constant in this process, in the corresponding in-vivo studies in rats, peptide (6) [Ala-Cpa-NMe-D-Cpa-NMe-Cpa-Cpa-4,4 difluro-D-Pro] exhibited M exposures at 3mg/kg and an absolute oral bioavailability of > 90%. Thus, we conclude the Cpa- and DiF-D-Pro residues are metabolically stable isosteres for Leu, and D-Pro respectively.

Item Type: Article
Keywords: Cyclic peptides, oral bioavailability, metabolism, pharmacokinetics
Date Deposited: 21 Apr 2020 00:45
Last Modified: 21 Apr 2020 00:45


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