The influence of drug-like concepts on decision-making in medicinal chemistry
The influence of drug-like concepts on decision-making in medicinal chemistry
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DOI：
10.1038/nrd2445
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发表时间：
2007-11-01
影响因子：
120.1
通讯作者：
Springthorpe, Brian
中科院分区：
文献类型：
--
作者：
Leeson, Paul D.;Springthorpe, Brian
应用与药物相似概念有关的指导方针，如“五条规则”，已被广泛接受，作为减少药物发现和开发中的消耗的一种方法。然而，尽管人们接受了这一点，但对最近趋势的分析表明，目前领先的药物发现公司正在合成的分子的物理性质与临床开发中最近发现的口服药物和化合物的物理性质有很大不同。亲脂性--最重要的类似药物的物理性质--显著增加的后果包括在药物开发中缺乏选择性和消耗性的可能性更大。应对与化合物相关的毒理磨损的威胁需要转向药物化学决策的主流。
The application of guidelines linked to the concept of drug-likeness, such as the 'rule of five', has gained wide acceptance as an approach to reduce attrition in drug discovery and development. However, despite this acceptance, analysis of recent trends reveals that the physical properties of molecules that are currently being synthesized in leading drug discovery companies differ significantly from those of recently discovered oral drugs and compounds in clinical development. The consequences of the marked increase in lipophilicity - the most important drug-like physical property - include a greater likelihood of lack of selectivity and attrition in drug development. Tackling the threat of compound-related toxicological attrition needs to move to the mainstream of medicinal chemistry decision-making.