Journal of Medicinal Chemistry p. 9316 - 9339 (2020)
Update date:2022-08-15
Topics: Chemical Synthesis In vitro Testing In Vivo Testing Pharmacokinetics Discovery Conformationally constrained Oxazolidinone
Zhao, Hongyi
Wang, Bin
Fu, Lei
Li, Gang
Lu, Haijia
Liu, Yuke
Sheng, Li
Li, Yan
Zhang, Baoxi
Lu, Yang
Ma, Chen
Huang, Haihong
Zhang, Dongfeng
Lu, Yu
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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