Intramolecular hydrogen bonding to improve membrane permeability and absorption in beyond rule of five chemical space
Intramolecular hydrogen bonding to improve membrane permeability and absorption in beyond rule of five chemical space
复制标题
DOI：
10.1039/c1md00093d
复制
发表时间：
2011-07-01
期刊：
影响因子：
--
通讯作者：
Whitlock, Gavin A.
中科院分区：
文献类型：
--
作者：
Alex, Alexander;Millan, David S.;Whitlock, Gavin A.
在药物设计中，利用“超越五规则”的化学空间变得越来越重要，但通常与良好的口服吸收不一致。药物分子中分子内氢键的形成被假设为屏蔽极性，从而促进膜渗透性和肠吸收的改善。基于核磁共振的证据，分子内氢键在几个'超越规则的五'口服药物。此外，这些药物形成分子内氢键的倾向可以通过模拟气相中的最低能量构象来预测。通过这些分子中的分子内氢键调节表观亲脂性得到了大鼠和人的固有细胞渗透性和肠吸收数据的支持。
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.