Discovery of a Conformationally Constrained Oxazolidinone with Improved Safety and Efficacy Profiles for the Treatment of Multidrug-Resistant Tuberculosis

被引:32
|
作者
Zhao, Hongyi [1 ]
Wang, Bin [2 ]
Fu, Lei [2 ]
Li, Gang [1 ]
Lu, Haijia [1 ]
Liu, Yuke [3 ]
Sheng, Li [3 ]
Li, Yan [3 ]
Zhang, Baoxi [4 ]
Lu, Yang [4 ]
Ma, Chen [5 ]
Huang, Haihong [1 ]
Zhang, Dongfeng [1 ]
Lu, Yu [2 ]
机构
[1] Chinese Acad Med Sci & Peking Union Med Coll, Chinese Acad Med Sci, Beijing Key Lab Act Subst Discovery & Druggabil E, Key Lab AntiDR TB Innovat Drug Res,Inst Mat Med, Beijing 100050, Peoples R China
[2] Capital Med Univ, Beijing Chest Hosp, Beijing TB & Thorac Tumor Res Inst, Beijing Key Lab Drug Resistance TB Res,Dept Pharm, Beijing 101149, Peoples R China
[3] Chinese Acad Med Sci & Peking Union Med Coll, Chinese Acad Med Sci, Beijing Key Lab Nonclin Drug Metab & PK PD Study, Key Lab AntiDR TB Innovat Drug Res,Inst Mat Med, Beijing 100050, Peoples R China
[4] Chinese Acad Med Sci & Peking Union Med Coll, Inst Mat Med, Beijing Key Lab Polymorph Drugs, Beijing 100050, Peoples R China
[5] Chinese Acad Med Sci & Peking Union Med Coll, Chinese Acad Med Sci, Beijing Key Lab Polymorph Drugs, Key Lab AntiDR TB Innovat Drug Res,Inst Mat Med, Beijing 100050, Peoples R China
基金
中国国家自然科学基金;
关键词
BENZOXAZINYL-OXAZOLIDINONES; MYCOBACTERIUM-TUBERCULOSIS; BACTERICIDAL ACTIVITY; IN-VITRO; POTENT; ANALOGS; DESIGN;
D O I
10.1021/acs.jmedchem.0c00500
中图分类号
R914 [药物化学];
学科分类号
100701 ;
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.
引用
收藏
页码:9316 / 9339
页数:24
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