含有环旋butan的共价BTK抑制剂的氨酸合物的宏观重排离子碎片化
Cathy A Muste1, Chungang Gu1, H George Vandeveer2
1Drug Metabolism and Pharmacokinetics, Biogen Inc., 225 Binney St, Cambridge, Massachusetts 02142, United States.
Journal of the American Society for Mass Spectrometry
|March 17, 2025
概括
联BTK抑制剂可以形成意想不到的谷二添加物. 在药物发现过程中,发现了一种涉及环联结剂的新型宏环重组机制,影响清除途径.
科学领域:
- 药用化学 医学化学
- 质谱测量质量谱测量
- 药物发现 药物发现 药物发现
背景情况:
- 共价BTK抑制剂利用活性烯胺弹头进行不可逆转的结合.
- 这种反应性导致对谷氨 (GSH) 结合和清除的敏感性.
- 在BIIB129开发过程中观察到意想不到的质谱碎片化.
研究的目的:
- 为了调查LC-MS/MS分析GSH adducts中的意外碎片离子的原因.
- 阐明了共价BTK抑制剂中新型宏循环重组的机制.
- 了解链接结构如何影响GSH adduct碎片化和稳定性.
主要方法:
- 使用LC-MS/MS对30多种共价BTK抑制剂及其GSH合物的分析.
- 合成和分析化学类似物,包括N-乙化和化GSH衍生物.
- 使用MS3和MS4碎片化技术来确认拟议的离子结构.
- 对 cis 和 trans 同体的碎片化模式进行比较,以确定反应机制.
主要成果:
- 确定了一种新的16个成员的宏循环重排机制,依赖于环链接器.
- 这种重新排列涉及GSH的g-glutamic 酸残留物和甲基-环丁乙.
- 对GSH (N-乙化,化) 和链接器立体化学的修改证实了拟议的机制.
结论:
- 循环连接器的存在决定了GSH adducts的一个独特的宏循环重排路径.
- 这种重新排列显著影响了LC-MS/MS分析中观察到的碎片化模式.
- 了解这种机制对于预测和管理共价抑制剂的代谢命运至关重要.
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