具有强大的抗грам阴性活性和最小的hERG抑制的新型印丹含有NBTI
John G Cumming1, Lukas Kreis1, Holger Kühne1
1Roche Pharma Research & Early Development, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland.
ACS medicinal chemistry letters
|December 20, 2023
概括
新型细菌拓酶抑制剂对抗耐药细菌显示出有前途. 优化的化合物表现出广泛的活性和低心脏风险,但异常的药理动力学限制了进一步的发展.
科学领域:
- 药用化学 医学化学
- 抗微生物耐药性研究研究
- 药理学 药理学是指药理学的学科.
背景情况:
- 新型细菌拓酶抑制剂 (NBTI) 代表了对抗微生物耐药性的潜在解决方案.
- 关键的挑战包括实现对抗格拉姆阴性细菌的广泛活性,并最大限度地降低hERG通道抑制.
研究的目的:
- 为了优化NBTI,使用一种新型的DNA插曲部分.
- 为了增强抗菌谱和减少hERG通道抑制.
主要方法:
- 通过以太或胺连接,对印丹部分进行基质,极端侧链的修改.
- 在酶结合区域的脂性降低.
- 在体外和体外疗效测试,包括小鼠肺部感染模型.
- 在动物中进行的药理动力学研究.
主要成果:
- 化合物2a和2g表现出广泛的功效和最小的hERG抑制.
- 化合物2a在体内显示出显著的杀菌活性,对抗多药耐药P. aeruginosa.
- 化合物2a在药理动力学研究中显示出快速组织分布和延长的终端阶段.
结论:
- 优化的NBTI显示出对抗耐药性格拉姆阴性细菌的潜力.
- 化合物2a的异常药理动力学特征阻止了其作为抗生素的进一步发展.
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