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

  • Ian Lewis
  • Michael Schaefer
  • Trixie Wagner
  • Lukas Oberer
  • Emine Sager
  • Peter Wipfli
  • Thomas Vorherr
Article

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.

Graphical Abstract

Keywords

Permeability Pharmacokinetics Cyclohexapeptides Conformation 

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

Notes

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.

Supplementary material

10989_2014_9447_MOESM1_ESM.pdf (662 kb)
Supplementary material 1 (PDF 661 kb)

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Ian Lewis
    • 1
  • Michael Schaefer
    • 1
  • Trixie Wagner
    • 1
  • Lukas Oberer
    • 1
  • Emine Sager
    • 1
  • Peter Wipfli
    • 1
  • Thomas Vorherr
    • 1
  1. 1.Novartis Institutes for Biomedical ResearchBaselSwitzerland

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