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口服PROTACs的结构和物理化学特征
Markus Schade1, James S Scott1, Thomas G Hayhow1
1Chemistry and DMPK, Oncology R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge CB2 0AA, United Kingdom.
Journal of medicinal chemistry
|July 30, 2024
概括
开发口服可用的蛋白质溶解向化马体 (PROTACs) 是很困难的. 这项研究引入了一项新规则,将暴露于溶剂的H键捐赠者 (eHBD) 限制在2,以改善口服PROTAC的生物可用性.
科学领域:
- 药用化学 医学化学
- 药理动力学 药理动力学
- 药物发现 药物发现 药物发现
背景情况:
- 实现蛋白质溶解向基马体 (PROTACs) 的口服生物可用性是药物开发中的一个重大障碍.
- 现有的药物开发规则可能不完全适用于PROTACs的独特结构特征.
研究的目的:
- 在临床前的物种中研究口服PROTACs的体内药理动力学特性.
- 在PROTAC中确定与口服生物可用性相关的关键分子描述剂.
- 建立用于设计口服生物可用PROTAC的实验指南.
主要方法:
- 在小鼠,老鼠和狗模型中评估了四种临床口服PROTAC的药理动力学概况.
- 利用核磁共振 (NMR) 来确定3D分子构造和预组织.
- 引入并量化了新的描述符:暴露于溶剂的键捐赠者 (eHBD) 和接受者 (eHBA).
主要成果:
- 在非极地环境中为口服PROTACs建立了eHBD ≤ 2的上限.
- 与传统口服药物相比,对其他特性 (如eHBA,极性,脂性和分子量) 具有更大的耐受性.
- 在PROTAC中观察到,在结构相关的系列中,eHBD> 2的口服生物利用率明显低于eHBD ≤ 2的PROTAC.
结论:
- 提出了一个实验性的"口服PROTACs规则",以指导药物化学家.
- 在PROTAC设计中,eHBD描述器对于实现口服生物可用性至关重要.
- 这一规则为增强PROTAC治疗药物的口服药物输送提供了实际框架.
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