药学学报, 2021, 56(11): 3030-3046
引用本文:
张蕊, 王江, 朱浩然, 柳红. 先导化合物结构优化策略(九)——改善药物清除率[J]. 药学学报, 2021, 56(11): 3030-3046.
ZHANG Rui, WANG Jiang, ZHU Hao-ran, LIU Hong. Lead compound optimization strategy (9) - reducing drug clearance through structure modification[J]. Acta Pharmaceutica Sinica, 2021, 56(11): 3030-3046.

先导化合物结构优化策略(九)——改善药物清除率
张蕊1,2, 王江1,2, 朱浩然1,2, 柳红1,2*
1. 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;
2. 中国科学院大学, 北京 100049
摘要:
清除率反映药物分子在体循环中被提取和消除的快慢程度。通过化学结构修饰方法降低化合物的清除率有助于改善化合物在体内的药代动力学和药效学性质。本文介绍了清除率的概念和研究意义,体内清除率的常见预测方法,重点综述了改善清除率的先导化合物结构优化策略,主要包括: 通过降低亲脂性、封闭代谢位点、骨架修饰、增加位阻等方法降低肝脏代谢转化清除率;通过提高亲脂性、降低极性表面积、生物电子等排等方法降低胆汁排泄清除率或肾脏排泄清除率;最后总结了药物分子立体构型对清除率的影响。
关键词:    清除率      肝脏代谢      排泄      亲脂性      立体构型     
Lead compound optimization strategy (9) - reducing drug clearance through structure modification
ZHANG Rui1,2, WANG Jiang1,2, ZHU Hao-ran1,2, LIU Hong1,2*
1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;
2. University of Chinese Academy of Sciences, Beijing 100049, China
Abstract:
Clearance reflects the speed of extraction and elimination of drug molecules from systemic circulation. Reducing the clearance of compounds using structure modification strategy could lead to good pharmacokinetic and pharmacodynamic properties. Herein, the concept of clearance, as well as several prediction methods of in vivo clearance are introduced. The strategies of reducing drug clearance are reviewed. These methods include reducing hepatic metabolic clearance through reducing lipophilicity, blocking metabolic site, scaffold modification and increasing steric hindrance; reducing biliary or renal excretion clearance through increasing lipophilicity, reducing polar surface area and bioisosterism. In addition, the influence of spatial configuration on drug clearance is also summarized.
Key words:    clearance    hepatic metabolism    excretion    lipophilicity    chiral configuration   
收稿日期: 2021-06-15
DOI: 10.16438/j.0513-4870.2021-0866
基金项目: 国家自然科学基金资助项目(21632008).
通讯作者: 柳红,Tel:86-21-50807042,E-mail:hliu@simm.ac.cn
Email: hliu@simm.ac.cn
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