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A Detailed Investigation on Conformation, Permeability and PK Properties of Two Related Cyclohexapeptides

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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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Correspondence to Ian Lewis.

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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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