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

J Med Chem. 2020 Sep 10;63(17):9316-9339. doi: 10.1021/acs.jmedchem.0c00500.

Hongyi Zhao ¹, Bin Wang ², Lei Fu ², Gang Li ¹, Haijia Lu ¹, Yuke Liu ³, Li Sheng ³, Yan Li ³, Baoxi Zhang ⁴, Yang Lu ⁴, Chen Ma ⁵, Haihong Huang ¹, Dongfeng Zhang ¹, Yu Lu ²

Affiliations

1 Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Chinese Academy of Medical Sciences Key Laboratory of Anti-DR TB Innovative Drug Research, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, P. R. China.
2 Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Department of Pharmacology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, 97 Ma Chang Street, Beijing 101149, P. R. China.
3 Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Chinese Academy of Medical Sciences Key Laboratory of Anti-DR TB Innovative Drug Research, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, P. R. China.
4 Beijing Key Laboratory of Polymorphic Drugs, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, P. R. China.
5 Beijing Key Laboratory of Polymorphic Drugs, Chinese Academy of Medical Sciences Key Laboratory of Anti-DR TB Innovative Drug Research, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, P. R. China.

PMID: 32666789 DOI: 10.1021/acs.jmedchem.0c00500

Abstract

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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