Discovery and preclinical profile of sudapyridine (WX-081), a novel anti-tuberculosis agent

  • Bioorg Med Chem Lett. 2022 Sep 1;71:128824. doi: 10.1016/j.bmcl.2022.128824.
Zhigang Huang  1 ,  Wei Luo  1 ,  Deming Xu  2 ,  Fengxun Guo  2 ,  Meng Yang  2 ,  Yusong Zhu  2 ,  Liang Shen  2 ,  Shuhui Chen  2 ,  Dongdong Tang  1 ,  Lei Li  3 ,  Yongguo Li  3 ,  Bin Wang  4 ,  Scott G Franzblau  5 ,  Charles Z Ding  6
Affiliations
  • 1. WuXi AppTec, 666 Gaoxin Road, East Lake High-tech Development Zone, Wuhan 430075, China.
  • 2. WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
  • 3. Shanghai Jiatan Biotech Ltd., a subsidiary of Guangzhou JOYO Pharma Ltd., Shanghai, China.
  • 4. Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China.
  • 5. Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, United States.
  • 6. WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China. Electronic address: [email protected].
PMID: 35636648 DOI: 10.1016/j.bmcl.2022.128824
Abstract

Multidrug resistant tuberculosis (MDR-TB) remains a major human health challenge. Bedaquiline was approved in 2012 by the US FDA, and listed by WHO as a treatment for multidrug-resistant tuberculosis (MDR-TB) in 2018. However, the side effects of bedaquiline including the risk of unexplained mortality, QTc prolongation and hepatotoxicity limit its wide clinical use. Based on bedaquiline, we describe herein discovery and development of a novel diarylpyridine series, which led to identification of WX-081 (sudapyridine, 21l). It displayed excellent anti-mycobacterial activity against M. tuberculosis H37Rv in vitro and in vivo and low cytotoxicity; additionally WX-081 had excellent pharmacokinetic parameters in Animals, better lung exposure and lower QTc prolongation potential compared to bedaquiline. WX-081 is currently under clinical phase II development (NCT04608955).

Keywords
Bedaquiline; MDR-TB; Mycobacterium tuberculosis; Sudapyridine; WX-081.
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