药理学
化学
可药性
体内
利福平
安全药理学
细胞色素P450
异烟肼
肺结核
酶
药品
生物化学
医学
抗生素
生物
生物技术
病理
基因
作者
Hongshan Zhao,Bin Wang,Ling Fu,Gang Li,Haijia Lu,Yuke Liu,Sheng Li,Yan Li,Baoxi Zhang,Lü Yang,Chen Ma,Huanwei Huang,Dongfeng Zhang,Yu Lu
标识
DOI:10.1021/acs.jmedchem.0c00500
摘要
Tuberculosis (TB) remains a serious public health challenge, and the research and development of new anti-TB drugs is an essential component of the global strategy to eradicate TB. In this work, we discovered a conformationally constrained oxazolidinone 19c with improved anti-TB activity and safety profile through a focused lead optimization effort. Compound 19c displayed superior in vivo efficacy in a mouse TB infection model compared to linezolid and sutezolid. The druggability of compound 19c was demonstrated in a panel of assays including microsomal stability, cytotoxicity, cytochrome P450 enzyme inhibition, and pharmacokinetics in animals. Compound 19c demonstrated an excellent safety profile in a battery of safety assays, including mitochondrial protein synthesis, hERG K+, hCav1.2, and Nav1.5 channels, monoamine oxidase, and genotoxicity. In a 4 week repeated dose toxicology study in rats, 19c appeared to have less bone marrow suppression than linezolid, which has been a major liability of the oxazolidinone class.
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