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. Epub 2022 May 27.

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.

Publication types

  • Clinical Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antitubercular Agents / pharmacology
  • Antitubercular Agents / therapeutic use
  • Long QT Syndrome* / chemically induced
  • Long QT Syndrome* / drug therapy
  • Mycobacterium tuberculosis*
  • Tuberculosis, Multidrug-Resistant* / drug therapy

Substances

  • Antitubercular Agents

Associated data

  • ClinicalTrials.gov/NCT04608955