摘要
在早期的药物研发过程中,由于当时条件和认识的局限,人们常将对应异构体当成单一光学纯化合物处理。随着手性拆分技术的发展以及人们对于手性药物认识的提高,手性对于药物的药理活性、毒性、代谢性质的影响逐渐被重视,一些与手性相关的不良反应事件发生,如欧洲＂反应停＂事件,使药物研发人员对药物中的手性因素更加关注。轴手性是手性的一种特殊形式,是由于空间位阻或电子效应导致共价键不能自由旋转而产生。轴手性对于化合物的药理活性、代谢性质也有广泛的影响,但由于分子中不具手性中心,而容易被忽视。药物研发是一个漫长而昂贵的过程,因此在早期阶段就应该给予轴手性足够的重视,最大的降低药物后期研发和临床试验的风险。对于具手性中心的手性药物,FDA已于1992年出台相关文件指导其研究开发,但是对于轴手性药物的研发却没有明确规定。本文从轴手性化合物的产生、构型判断、轴手性-活性关系以及轴手性药物发展趋势4个方面对轴手性化合物的研究进展进行综述和探讨,阐述轴手性在药物研发过程中的重要性,为轴手性药物的研究和开发提供参考。
Objective： In the early stages of drug research and development,the enantiomers were usually treated as a single optical pure compound due to the limitations of knowledge and conditions. With the development of chiral separation technology and the increasing awareness of chiral drugs,the effects of chirality on pharmacological activity,toxicity,and metabolic properties of drugs have been gradually regarded. Several adverse reactions due to the chirality,such as the ‘thalidomide event＇in Europe,have led drug developers to pay more attention to chiral factors in drugs. Axial chirality is a special form of chirality,where the covalent bond cannot rotate freely due to steric hindrance or electronic effects. Axial chirality also has extensive effects on pharmacological activity and metabolic properties of compounds,but it is usually neglected since the molecule does not possess a stereogenic center. Drug research and development is a lengthy and expensive process. Therefore,axis chirality should be paid enough attention in the early stage to minimize the risks in advanced development and clinical trials. For chiral drugs,FDA has issued relevant documents to guide the research and development since1992. However,there is no specific provision for the development of axial-chiral drugs. In this paper,the progress of axis-chiral drugs research is reviewed and discussed from four aspects： generation,configuration judgment,axial chirality-activity relationship,and development trend of axis-chiral drugs. The importance of axis-chirality in the process of drug research and development is also discussed,which is of reference value for the research and development of axis-chiral drugs.
作者
苏海国
周勤梅
沈垠桥
郭力
戴鸥
SU Hai-guo;ZHOU Qin-mei;SHEN Yin-qiao;GUO Li;DAI Ou(College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Key Laboratory of Standardization of Chinese Herbal Medicine of Ministry of Education, State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu 611137, China)
出处
《中国实验方剂学杂志》
CAS
CSCD
北大核心
2018年第1期201-208,共8页
Chinese Journal of Experimental Traditional Medical Formulae
基金
四川省青年科技创新研究团队专项计划项目(2017TD0001)
关键词
轴手性
阻转异构
活性差异
构型判断
axial chirality
atropisomerism
activity difference
configuration judgment
