Jump to main content
Jump to site search
Publishing
Advanced

Issue 7, 2011
Previous Article Next Article

Intramolecular hydrogen bonding to improve membrane permeability and absorption in beyond rule of five chemical space†

Alexander Alex,a   David S. Millan,*a   Manuel Perez,a   Florian Wakenhuta  and  Gavin A. Whitlocka  
Author affiliations

* Corresponding authors

a Worldwide Medicinal Chemistry, Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Kent, UK
E-mail: david.millan@pfizer.com

Abstract

Utilising ‘beyond rule of five’ chemical space is becoming increasingly important in drug design, but is usually at odds with good oral absorption. The formation of intramolecular hydrogen bonds in drug molecules is hypothesised to shield polarity facilitating improved membrane permeability and intestinal absorption. NMR based evidence for intramolecular hydrogen bonding in several ‘beyond rule of five’ oral drugs is described. Furthermore, the propensity for these drugs to form intramolecular hydrogen bonds could be predicted for through modelling the lowest energy conformation in the gas phase. The modulation of apparent lipophilicity through intramolecular hydrogen bonding in these molecules is supported by intrinsic cell permeability and intestinal absorption data in rat and human.

Graphical abstract: Intramolecular hydrogen bonding to improve membrane permeability and absorption in beyond rule of five chemical space

Back to tab navigation
Download options Please wait...

Supplementary files

Publication details

The article was received on 31 Mar 2011, accepted on 22 Apr 2011 and first published on 20 May 2011


Article type: Concise Article
DOI: 10.1039/C1MD00093D
Med. Chem. Commun., 2011,2, 669-674

  •   Request permissions

    Intramolecular hydrogen bonding to improve membrane permeability and absorption in beyond rule of five chemical space

    A. Alex, D. S. Millan, M. Perez, F. Wakenhut and G. A. Whitlock, Med. Chem. Commun., 2011, 2, 669
    DOI: 10.1039/C1MD00093D

    If you are not the author of this article and you wish to reproduce material from it in a third party non-RSC publication you must formally request permission using Copyright Clearance Center. Go to our Instructions for using Copyright Clearance Center page for details.

    Authors contributing to RSC publications (journal articles, books or book chapters) do not need to formally request permission to reproduce material contained in this article provided that the correct acknowledgement is given with the reproduced material.

    Reproduced material should be attributed as follows:

    • For reproduction of material from NJC:
      Reproduced from Ref. XX with permission from the Centre National de la Recherche Scientifique (CNRS) and The Royal Society of Chemistry.
    • For reproduction of material from PCCP:
      Reproduced from Ref. XX with permission from the PCCP Owner Societies.
    • For reproduction of material from PPS:
      Reproduced from Ref. XX with permission from the European Society for Photobiology, the European Photochemistry Association, and The Royal Society of Chemistry.
    • For reproduction of material from all other RSC journals and books:
      Reproduced from Ref. XX with permission from The Royal Society of Chemistry.

    If the material has been adapted instead of reproduced from the original RSC publication "Reproduced from" can be substituted with "Adapted from".

    In all cases the Ref. XX is the XXth reference in the list of references.

    If you are the author of this article you do not need to formally request permission to reproduce figures, diagrams etc. contained in this article in third party publications or in a thesis or dissertation provided that the correct acknowledgement is given with the reproduced material.

    Reproduced material should be attributed as follows:

    • For reproduction of material from NJC:
      [Original citation] - Reproduced by permission of The Royal Society of Chemistry (RSC) on behalf of the Centre National de la Recherche Scientifique (CNRS) and the RSC
    • For reproduction of material from PCCP:
      [Original citation] - Reproduced by permission of the PCCP Owner Societies
    • For reproduction of material from PPS:
      [Original citation] - Reproduced by permission of The Royal Society of Chemistry (RSC) on behalf of the European Society for Photobiology, the European Photochemistry Association, and RSC
    • For reproduction of material from all other RSC journals:
      [Original citation] - Reproduced by permission of The Royal Society of Chemistry

    If you are the author of this article you still need to obtain permission to reproduce the whole article in a third party publication with the exception of reproduction of the whole article in a thesis or dissertation.

    Information about reproducing material from RSC articles with different licences is available on our Permission Requests page.

Search articles by author

Spotlight

Advertisements