氰基在药物分子设计中的应用有机化学.pdfVIP

DOI: 10.6023/cjoc1202132 综述与进展 有机化学 Chinese Journal of Organic Chemistry REVIEW 氰基在药物分子设计中的应用 王 江 柳 红* ( 中国科学院上海药物研究所新药研究国家重点实验室 上海 201203) 摘要 含氰基药物在临床治疗药物中占有相当比重. 将氰基基团引入到小分子药物中是药物化学结构改造的重要研究 策略之一. 综述了氰基在药物分子设计中的应用, 氰基的引入可以调节小分子药物的物理化学特性, 改变小分子的药 代动力学性质, 提高药物的生物利用度; 通过氢键相互作用、共价相互作用、偶极相互作用以及 π-π相互作用增强配体 与靶标蛋白的相互结合能力以及对其它靶标蛋白的选择性; 同时, 氰基是羰基、卤素等多种官能团的生物电子等排体; 将氰基引入到药物小分子当中, 可以通过阻断易代谢位点进而提高药物代谢稳定性等. 关键词 氰基; 药物设计; 结构优化 Application of Nitrile in Drug Design Wang, Jiang Liu, Hong* (State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203) Abstract Nitrile-containing compounds comprise a substantial proportion in the therapeutic drugs. It is an important strategy to introduce nitrile substitute in the small molecule for structure-based medicinal chemistry. The application of nitrile in drug design is reviewed. The nitrile can modulate the physicochemical and pharmacokinetic properties to improve bioavailability, enhance the selectivities and binding affinity to target proteins by hydrogen bond interactions, covalent interactions, polar in- teractions, and π-π interactions. Meanwhile, the nitrile acts as bioisostere of various functional groups such as carbonyl and halogen groups. In addition, introducing the nitrile to drug molecules can block metabolically labile sites to increase the meta- bolic stability of drugs. Keywords nitrile; drug design; lead optimization 目前, 许多临床使用的药物中都含有氰基基团. 氰