宝石二化对模型宏观循环系统的形状和特性的影响
T J Cogswell1, R J Lewis2, C Sköld3
1Medicinal Chemistry, Early Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca Gothenburg Sweden thomas.cogswell@acerta-pharma.com laurent.knerr@astrazeneca.com.
Chemical science
|November 21, 2024
概括
将二醇基基分子引入宏循环可以改变它们的构造,可能会影响药物特性. 这项研究比较了化和非化宏循环,揭示了形状变化和代谢稳定性差异.
科学领域:
- 药用化学 医学化学
- 有机化学 有机化学
- 药物发现 药物发现 药物发现
背景情况:
- 符合性控制是提高药物效能和ADME特性的关键.
- 宏循环提供了刚性,使得它们非常适合构造性操纵.
- 该研究将二醇基基组作为一种用于修改宏环形状的新型工具.
研究的目的:
- 为了研究二甲基基基部分对宏环形状的影响.
- 为了比较化和非化宏环对的结构偏好和ADME特性.
- 阐明这些宏观循环中的构造和代谢稳定性之间的关系.
主要方法:
- 化和非化宏环化合物的合成.
- 使用1HNMR光谱的合规分析.
- 评估代谢稳定性和ADME特性.
主要成果:
- 这两种宏观循环都采用了类似的主要形状,其中含有甲基.
- 化宏环在平衡状态下表现出较小的cis胺基构造 (4:1 trans/cis比率).
- 二甲基组对外平面方向的偏好影响了cis胺基的形成.
- 与非化对应物相比,化宏环的代谢稳定性降低.
结论:
- 二醇基基部分可以诱导宏循环中的结构变化,有利于cis胺基的形成.
- 在化宏循环中观察到的构造平衡与其降低的代谢稳定性有关.
- 这一小部分代表了微调宏循环药物候选特性的潜在策略,尽管代谢影响需要仔细考虑.
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