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

作者：Alexander Alex, David S. Millan, Manuel Pérez, Florian Wakenhut, Gavin A. Whitlock · 发表于：MedChemComm · 年份：2011 · DOI：10.1039/c1md00093d · 被引用次数：332 · 研究领域：Synthesis and biological activity、Synthesis and Characterization of Heterocyclic Compounds、DNA and Nucleic Acid Chemistry

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.