Abstract
This contribution provides detailed insights regarding permeability properties of published cyclohexapeptides related to their conformation. The study includes data on oral bioavailability and PK parameters including application of a known enhancer. Interestingly, the latter did not show an effect, neither on the cyclic peptide exhibiting low oral uptake nor on the similar molecule showing a 30 % oral bioavailability in mice. These results are discussed in the context of exposed polar surface area for the preferred conformation and structural data obtained by NMR and X-ray crystallography.
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Abbreviations
- Boc:
-
Tert-butyloxylcarbonyl
- BAV:
-
Bioavailability on p.o. administration
- CH3CN:
-
Acetonitrile
- CL:
-
In-vitro or in vivo clearance
- CsA:
-
Cyslosporine A
- DCM:
-
Dichloromethane
- DIEA:
-
DIPEA diisopropyl ethylamine
- DMF:
-
Dimethyl formamide
- DDM:
-
Dodecylmaltoside enhancer
- LiOtBu:
-
Lithium t-butoxide
- NOESY:
-
Nuclear Overhauser effect spectroscopy
- PAMPA:
-
Parallel artificial membrane permeability assay
- MDCK:
-
Madin Darby canine kidney cells
- PPB:
-
Plasma–protein binding
- rmsd:
-
Root mean squared deviation
- p.o.:
-
Per os
- Rh:
-
Hydrodynamic radius
- ROESY:
-
NOE in the rotating frame
- RPHPLC:
-
Reversed-phase high performance liquid chromatography
- SAPSA:
-
Solvent-accessible polar surface area
- SFC:
-
Supercritical fluid chromatography
- TFA:
-
Trifluoroacetic acid
- TLC:
-
Thin layer chromatography
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Acknowledgments
The excellent support of Sandrine Desrayaud, Valerie Cordier, Elisabeth Braun, Laurent Hoffmann and Francis Risser is gratefully acknowledged. We thank Armin Widmer (armin.widmer@novartis.com) for the molecular modeling program Witnotp.
Conflict of interest
Ian Lewis, Michael Schaefer, Trixie Wagner, Lukas Oberer, Emine Sager, Peter Wipfli and Thomas Vorherr declare that they have no conflict of interest concerning Human and Animal Rights and Informed Consent.
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Standard abbreviations for amino acids and peptide derivatives are according to the suggestion of the IUPAC-IUB Joint commission on Biochemistry Nomenclature: Eur. J. Biochem. 138 (1984) 9–37.
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Lewis, I., Schaefer, M., Wagner, T. et al. A Detailed Investigation on Conformation, Permeability and PK Properties of Two Related Cyclohexapeptides. Int J Pept Res Ther 21, 205–221 (2015). https://doi.org/10.1007/s10989-014-9447-3
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DOI: https://doi.org/10.1007/s10989-014-9447-3