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New Perspective in Peptide Chemistry by N-Alkylation

  • Horst Kessler
  • Jayanta Chatterjee
  • Lucas Doedens
  • Florian Opperer
  • Eric Biron
  • Daniel Hoyer
  • Herbert Schmid
  • Chaim Gilon
  • Victor J. Hruby
  • Dale F. Mierke
Part of the Advances in Experimental Medicine and Biology book series (volume 611)

Introduction

Oral bioavailability is a major concern in the development of peptide based drugs. Peptides usually possess high selectivity and potency but the major drawback in their development as a drug is the extremely low oral availability. Insufficient bioavailability of peptides is caused by low membrane permeation, low uptake via tight junctions (paracellular transport), and active export into the gut and/or low resistance against enzymatic degradation. To circumvent these undesired properties, we envisioned the approach of multiple N-methylation. We were inspired by the cyclic peptide drug Cyclosporin which is administered orally and has seven of its eleven amide bonds N-methylated, and it violates all of the Lipinski's rules [1], for governing oral availability. Mono N-methylation has been employed over the years to improve lipophilicity, bioavailability, proteolytic stability and activity of peptides [2]. However, to our knowledge multiple N-methylation has never been...

Keywords

Oral Bioavailability Cyclic Peptide Metabolic Stability Paracellular Transport Oral Availability 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgment

We gratefully acknowledge the Humboldt Foundation for the support via the Max-Planck Forschungspreis. This work was also in part supported by the German Israel Foundation (GIF) and the Center of Integrated Protein Science Munich.

References

  1. 1.
    Lipinski, C. A., Lombardo, F., Dominy, B. W., Feeney, P. J. Adv. Drug Delivery Rev. 1997, 23, 3–25.CrossRefGoogle Scholar
  2. 2.
    Fairlie, D. P.; Abbenante, G.; March, D. R. Curr. Med. Chem. 1995, 2, 654–686.Google Scholar
  3. 3.
    Teixido, M.; Albericio, F.; Giralt, E. J. Pep. Res. 2005, 65, 153–166.CrossRefGoogle Scholar
  4. 4.
    Chatterjee, J.; Mierke, D.; Kessler, H. J. Am. Chem. Soc. 2006, 128, 15164–15172.CrossRefGoogle Scholar
  5. 5.
    Veber, D. F. et al. Nature 1981, 292, 55–58.CrossRefGoogle Scholar
  6. 6.
    Afargan, M. et al. Endocrinology. 2001, 142(1), 477–486.CrossRefGoogle Scholar
  7. 7.
    Bauer, W.; Briner, U.; Doepfner, W.; Haller, R.; Huguenin, R.; Marbach, P.; Petcher, T. J.; Pless, J. Life Sci. 1982, 31, 1133–1140CrossRefGoogle Scholar
  8. 8.
    Al-Obeidi, F.; Hadley, M. E.; Pettitt, B. M.; Hruby, V. J. J. Am. Chem. Soc. 1989, 111, 3413–3416.CrossRefGoogle Scholar
  9. 9.
    Chatterjee, J.; Ovadia, O.; Zahn, G.; Marinelli, L.; Hoffman, A.; Gilon, C.; Kessler, H. (manuscript in preparation).Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Horst Kessler
    • 3
  • Jayanta Chatterjee
    • 3
  • Lucas Doedens
    • 3
  • Florian Opperer
    • 3
  • Eric Biron
    • 3
  • Daniel Hoyer
    • 1
  • Herbert Schmid
    • 1
  • Chaim Gilon
    • 2
  • Victor J. Hruby
    • 3
  • Dale F. Mierke
    • 4
  1. 1.Novartis Institutes of Biomedical ResearchBaselSwitzerland
  2. 2.Organic Chemistry DepartmentThe Hebrew University of JerusalemIsraelJerusalem
  3. 3.Department of ChemistryThe University of ArizonaTucsonUSA
  4. 4.Department of Molecular PharmacologyBrown UniversityProvidenceUSA

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