先导化合物结构优化策略(四)——改善化合物的血脑屏障通透性

Lead compound optimization strategy(4)——improving blood-brain barrier permeability through structural modification

血脑屏障是人体的天然屏障,它在保护中枢神经系统免受外来物质干扰和伤害的同时,也阻碍了许多潜在的中枢神经系统药物进入中枢,增加了中枢神经系统药物研发的难度。本文简述了化合物透过血脑屏障研究的最新进展,从药物化学角度综述了几种通过结构优化改善化合物透过血脑屏障的方法,旨在为中枢神经系统药物的优化提供思路。常用的几种改善化合物血脑屏障通透性的策略包括:增加脂溶性、减少氢键供体、简化分子、增加刚性、降低极性表面积、剔除羧基、前药策略、修饰为主动转运体底物及规避易被P-糖蛋白识别的结构等。

Blood-brain barrier is a natural protection for human body. It protects central nervous system from the interruption and damage of xenobiotics. However, it prevents potential drugs aimed at central nervous system, thus becomes an obstruction for the development of central nervous system drugs. The recent development of blood-brain barrier permeability research and several lead optimization strategies to improve blood-brain barrier permeability are reviewed. These structure optimization methods include increasing lipophilicity, reducing hydrogen bond doners, simplifying molecule, increasing rigidity, lowering polar surface area, avoiding acid group, prodrug strategy, modifying into active transporter＇s substrates, as well as avoiding P-glycoorotein recognized structures.