2. Academic Validation
  3. Discovery and preclinical profile of sudapyridine (WX-081), a novel anti-tuberculosis agent

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

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: charles_ding@wuxiapptec.com.
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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