水溶性和可预测释放的三类前药物在小鼠中阻断了白胺诱导的肺纤维化
Yuhan Chen1, Meiyu Liang1, Wen Li1
1College of Health Science and Engineering, National & Local Joint Engineering Research Center of High-Throughput Drug Screening Technology, Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, Hubei University, Wuhan, 430062, China.
European journal of medicinal chemistry
|September 12, 2024
概括
新的三化物 (TP) 衍生物TP-DEA提供了更好的水溶性和酶独立转化为TP. TP-DEA2在体内有效抑制纤维化,显示出治疗异常性肺纤维化 (IPF) 的前景.
科学领域:
- 药用化学 医学化学
- 药理学 药理学是指药理学的学科.
- 肺部医学 肺部医学
背景情况:
- 异形性肺纤维化 (IPF) 是一种进展性肺病,治疗选择有限.
- ptolide (TP) 具有抗炎和抗纤维素特性,但具有不良的溶解性和副作用.
- 现有的TP前药物依赖于酶代谢,导致物种特定的变异性.
研究的目的:
- 合成具有酶独立激活的新型水溶性三类衍生物 (TP-DEAs).
- 评估这些TP衍生物在IPF治疗中的体外和体内疗效和安全性.
主要方法:
- 通过引入乙二胺碳酸基,合成TP衍生物 (TP-DEA).
- 在体外评估水溶性,稳定性和酶独立转化.
- 在体外评估抑制ADAM10和a-SMA分泌.
- 在体内研究,使用小鼠在白胺诱导的肺纤维化模型.
主要成果:
- TP-DEA2显著提高了水溶性 (>1181倍增加) 和稳定性.
- 在没有酶参与的情况下,TP-DEA2在体外自发转化为TP.
- TP-DEA2抑制了TGF-β1诱导的ADAM10表达,并降低了纤维细胞中的a-SMA分泌.
- 在体内,TP-DEA2有效降低了白胺诱导的肺纤维化,没有观察到毒性.
结论:
- TP-DEA2是一种有前途的,水溶性三类衍生物,具有酶独立的激活.
- 在体外和体内,TP-DEA2表现出强大的抗纤维性作用.
- TP-DEA2的疗效,即使在疾病模型中稍后给予,也表明其作为IPF治疗剂的潜力.
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