阿托品
轴手性
手性(物理)
对映体
化学
药物发现
位阻效应
非对映体
立体化学
对映选择合成
物理
有机化学
对称性破坏
量子力学
手征对称破缺
催化作用
生物化学
Nambu–Jona Lasinio模型
作者
Steven R. LaPlante,Paul Edwards,L. D. Fader,Araz Jakalian,Oliver Hucke
出处
期刊:ChemMedChem
[Wiley]
日期:2011-01-05
卷期号:6 (3): 505-513
被引量:392
标识
DOI:10.1002/cmdc.201000485
摘要
Abstract An often overlooked source of chirality is atropisomerism, which results from slow rotation along a bond axis due to steric hindrance and/or electronic factors. If undetected or not managed properly, this time‐dependent chirality has the potential to lead to serious consequences, because atropisomers can be present as distinct enantiomers or diastereoisomers with their attendant different properties. Herein we introduce a strategy to reveal and classify compounds that have atropisomeric chirality. Energy barriers to axial rotation were calculated using quantum mechanics, from which predicted high barriers could be experimentally validated. A calculated rotational energy barrier of 20 kcal mol −1 was established as a suitable threshold to distinguish between atropisomers and non‐atropisomers with a prediction accuracy of 86 %. This methodology was applied to subsets of drug databases in the course of which atropisomeric drugs were identified. In addition, some drugs were exposed that were not yet known to have this chiral attribute. The most valuable utility of this tool will be to predict atropisomerism along the drug discovery pathway. When used in concert with our compound classification scheme, decisions can be made during early discovery stages such as “hit‐to‐lead” and “lead optimization,” to foresee and validate the presence of atropisomers and to exercise options of removing, further stabilizing, or rendering the chiral axis of interest more freely rotatable via SAR design, thereby decreasing this potential liability within a compound series. The strategy can also improve drug development plans, such as determining whether a drug or series should be developed as a racemic mixture or as an isolated single compound. Moreover, the work described herein can be extended to other chemical fields that require the assessment of potential chiral axes.
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