On the Importance of Metabolic Stability to Achieve High Oral Exposures for Cyclic Peptides

Author Info

Felix Huth Ian Lewis Joachim Blanz Joerg Berghausen Kirsten Schroer Michael Schaefer Reiner Aichholz Roman Wille Thomas Vorherr Thomas Lochmann

Corresponding Author

Thomas Vorherr
Novartis Institutes for Biomedical Research, CH-4002 Basel, Switzerland

A B S T R A C T

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 mM exposures at 3mg/kg and an absolute oral bioavailability of > 90%. Thus, we emphasize the importance of controlling metabolism to achieve significant systemic exposure upon oral administration and suggest the Cpa- and DiF-D-Pro residues as metabolically stable isosteres for Leu, and D-Pro respectively.

Article Info

Article Type

Research Article

Publication history

Received: Mon 16, Dec 2019
Accepted: Thu 02, Jan 2020
Published: Thu 30, Jan 2020

Copyright

© 2023 Thomas Vorherr. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Hosting by Science Repository.
DOI: 10.31487/j.AJMC.2019.01.01