反转录酶的皮科莫拉抑制剂具有显著改善的代谢稳定性
Ya-Li Sang1,2,3, Christophe Pannecouque4, Erik De Clercq4
1Department of Chemistry, Engineering Center of Catalysis and Synthesis for Chiral Molecules, Fudan University, Shanghai 200433, China.
Acta pharmaceutica Sinica. B
|July 31, 2023
概括
研究人员通过添加基甲基侧链来改善抗艾滋病毒药物的代谢稳定性. 新的化合物9g显示出显著增强的稳定性和强烈的活性,对抗具有良好的安全性概况的耐药HIV-1菌株.
科学领域:
- 药用化学 医学化学
- 病毒学 病毒学
- 药理学 药理学是指药理学的学科.
背景情况:
- 非核类逆转录酶抑制剂 (NNRTIs) 在HIV-1治疗中至关重要.
- 化合物5,最近发现的NNRTI,表现出较差的代谢稳定性 (t1/2 = 96分钟).
- 改善代谢稳定性是开发有效和持久的抗艾滋病毒疗法的关键.
研究的目的:
- 增强NNRTI的新陈代谢稳定性 5.
- 为了合成具有改善药理动力学特性的新型甲基醇-二-二-二甲基胺.
- 评估新化合物的抗HIV-1活性,耐药性,细胞毒性和安全性.
主要方法:
- 新型甲基醇-双-二基胺衍生物的化学合成.
- 使用人类肝脏显微体进行体外代谢稳定性测试.
- 对野生型 (WT) 和耐药HIV-1菌株的抗病毒活性测试 (EC50确定).
- 细胞毒性测定 (CC50确定) 和选择性指数 (SI) 计算.
- 分子对接研究以阐明结合相互作用.
- 对CYP酶和hERG通道的抑制试验.
- 在小鼠中的急性毒性研究.
主要成果:
- 一系列的新型甲基醇-双-二-二基胺酸被合成.
- 化合物9g显著改善了代谢稳定性 (t1/2 = 2754分钟),与化合物5相比增加了29倍.
- 化合物9g对WT HIV-1 (EC50 = 0.9 nmol/L) 呈现强烈的皮科莫尔抑制和对五种耐药菌株的低纳米分子活性.
- 化合物9g显示出低细胞毒性 (CC50 = 264 μmol/L) 和高选择性指数 (SI = 256,438).
- 分子对接揭示了9g的增强结合稳定性,这是由于新的键相互作用.
- 化合物9g没有显著抑制CYP酶或hERG,并且在高剂量 (2g/kg) 的小鼠中没有毒性.
结论:
- 引入基甲基侧链有效提高了NNRTI的代谢稳定性.
- 化合物9g是新一代抗HIV-1药物的有希望的候选者,因为它具有强大的活性,改善的药理动力学和有利的安全性.
- 这些发现支持进一步开发这种类型的化合物用于治疗艾滋病毒.
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