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Issue 7, 2011
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Intramolecular hydrogen bonding to improve membrane permeability and absorption in beyond rule of five chemical space

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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

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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

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    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

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