作为COVID-19潜在治疗方法的卢福特雷尔维尔的早期临床开发
Christophe Allais1, David Bernhardson1, Adam R Brown1
1Chemical Research and Development, Pfizer Inc., Groton, Connecticut06340, United States.
概括
作为COVID-19候选药物的Lufotrelvir面临着稳定性问题. 除了DMSO溶解物外,还开发了工艺改进和新型合成路径,以确保药物的稳定性和纯度,以便有效治疗.
科学领域:
- 药用化学 医学化学
- 过程化学 过程化学
- 药物开发 药物开发
背景情况:
- 卢福特雷尔维尔是一种新的3CL蛋白酶抑制剂,旨在用于COVID-19治疗.
- 药物开发受阻于lufotrelvir的不稳定性,特别是表皮化和降解.
研究的目的:
- 为了克服发展中的稳定性挑战.
- 优化关键片段和最终产药的合成路径.
- 建立污染物控制和长期储存的方法.
主要方法:
- 改善了印和乳碎片的合成,包括对印进行Cu-催化C-O合.
- 使用的克莱森添加剂用于乳糖同质化和酸化以形成前药物.
- 识别和分离特定的溶剂形式 (MEK和DMSO),以保持稳定性和控制杂质.
主要成果:
- 成功增强关键的lufotrelvir前体的供应路线.
- 开发了一种稳定的DMSO溶解物形式的lufotrelvir,使长期存储.
- 实现了对与工艺相关的杂质的严格控制,适用于亲肠道配方.
结论:
- 工艺开发成功地解决了lufotrelvir的稳定性和杂质挑战.
- 鉴定DMSO溶盐对于该药物的长期可行性至关重要.
- 优化的合成策略和杂质控制为lufotrelvir的治疗应用铺平了道路.
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