鉴定和生物合成Camonsertib的一个N-Glucuronide代谢物
Robert Papp1, Laird Trimble2, Adrian J Fretland3
1Drug Metabolism and Pharmacokinetics, Repare Therapeutics, Inc., Canada RPAPP@REPARERX.COM.
Drug metabolism and disposition: the biological fate of chemicals
|February 20, 2024
概括
研究人员确定并描述了一种新型的N-glucuronide代谢物camonsertib,一个ATR激酶抑制剂. 该代谢物使用细菌培养物合成,其结构由NMR阐明,有助于开发用于晚期癌症的药物.
科学领域:
- 药理学和药物新陈代谢
- 有机化学 有机化学
- 生物化学 生物化学
背景情况:
- 卡蒙塞尔蒂布是一种研究中的ATR激酶抑制剂,用于治疗晚期癌症.
- 了解药物代谢对于治疗开发和安全至关重要.
- 葡萄糖化是药物清除的主要代谢途径.
研究的目的:
- 为了识别和阐明一种新的Camonsertib代谢物的结构.
- 为代谢物开发一种可扩展的生物合成方法.
- 为临床试验中的生物分析方法提供参考标准.
主要方法:
- 人类肝细胞化以检测代谢物.
- 隔离和净化N-葡萄胺代谢物.
- 准备性染色学和细菌培养用于扩大规模.
- 一维和二维NMR (H,C,NOE,HMBC) 用于结构阐明.
- 分子建模用于结构确认.
主要成果:
- 在人类肝细胞化中发现了camonsertib的N-glucuronide代谢物.
- 一种新的细菌培养方法使代谢物的可扩展生物合成成为可能.
- 使用先进的NMR技术确定了N-葡萄胺代谢物的完整结构.
- 合成的代谢物作为生物分析量化的标准.
结论:
- 这项研究报告了camonsertib的第一个确定的葡萄糖化物代谢物.
- 一种强大的细菌培养方法促进了用于研究的代谢物生产.
- 对N-glucuronide代谢物的结构阐明对于camonsertib的临床发展至关重要.
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