先导化合物结构优化策略(五)——降低药物hERG心脏毒性.pdf

1530 药学学报 Acta Pharmaceutica Sinica 20 16, 51 ( 10): 1530 1539 导化合物结构优化策略 ( 五) 降低药物hERG 心脏毒性 周圣斌, 王 江, 柳 红* ( 中国科学院上海药物研究所、受体结构与功能重点实验室, 上海 20 1203) 摘要: 由人类果蝇相关基因 (hERG) 编码的钾离子通道在人类生理、病理过程中扮演着十分重要的角色。 在心肌细胞中, hERG 钾通道影响心脏动作电位的复极过程。近年来, 一些药物因阻断该通道引起QT 间期延长 而被撤市。本文总结了降低与hERG 相关心脏毒性的先导化合物结构优化策略, 包括: 降低脂溶性、降低碱性、 引入羟基、引入酸性基团以及构象限制等。 关键词: 人类果蝇相关基因; 先导化合物结构优化; 脂溶性; 碱性; 构象限制; 心脏毒性 中图分类号: R9 16 文献标识码: A 文章编号: 0513-4870 (20 16) 10- 1530-10 Lead compound optimization strategy (5) –reducing the hERG cardiac toxicity in drug development * ZHOU Sheng-bin, WANG Jiang, LIU Hong (Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Ac ademy of S ciences, Shanghai 201203, China ) Abstract : The potassium channel encoded by the human ether-a-go-go related gene (hERG) plays a very important role in the physiological and pathological processes in human. hERG potassium channel determines the outward currents which facilitate the repolarization of the myocardial cells. Some drugs were withdrawn from the market for the serious side effect of long QT interval and arrhythmia due to blockade of hERG channel. The strategies for lead compound optimization are to reduce inhibitory activity of hERG potassium channel and decrease cardiac toxicity. These methods include reduction of lipophilicity and basicity of amines, introduction of hydroxyl and acidic groups, and restricting conformation.