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<p>Although benzbromarone is a highly potent inhibitor of URAT1, the toxicity of its metabolite has led to the restricted use. In this study, to decrease its toxicity, thirteen benzbromarone derivatives were designed and synthesized via blocking metabolic site. Among them, most of the compounds had moderate to strong inhibitory activity against URAT1, with IC<sub>50</sub> values ranging from 0.041 ± 0.010 μM to 3.208 ± 0.458 μM. In particular, compound <b>30</b> demonstrated the most potent URAT1-inhibitory activity (IC<sub>50</sub> = 0.041 ± 0.010 μM), which is nearly seven-fold enhanced over BBR (IC<sub>50</sub> = 0.278 ± 0.053 μM). Importantly, it displayed a favorable bioavailability of 75.2%. As demonstrated by the in vitro and in vivo experiments, no reported toxic metabolites were found and the risk of potential liver toxicity was low.</p><p></p>

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Discovery of novel benzbromarone derivatives via the closed metabolic site as potent human uric acid transporter 1 (URAT1) inhibitors

  • 期刊论文

  • 发表日期：

    2025年2月28日

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  • Wenfeng Ye,
  • Mingchao He,
  • Gaofeng Lin,
  • Li Shao,
  • Jiajia Mo,
  • Yan Zhao,
  • Xiaodong Ma,
  • Qinlong Xu,
  • Zhaoxing Chu

摘要

Although benzbromarone is a highly potent inhibitor of URAT1, the toxicity of its metabolite has led to the restricted use. In this study, to decrease its toxicity, thirteen benzbromarone derivatives were designed and synthesized via blocking metabolic site. Among them, most of the compounds had moderate to strong inhibitory activity against URAT1, with IC50 values ranging from 0.041 ± 0.010 μM to 3.208 ± 0.458 μM. In particular, compound 30 demonstrated the most potent URAT1-inhibitory activity (IC50 = 0.041 ± 0.010 μM), which is nearly seven-fold enhanced over BBR (IC50 = 0.278 ± 0.053 μM). Importantly, it displayed a favorable bioavailability of 75.2%. As demonstrated by the in vitro and in vivo experiments, no reported toxic metabolites were found and the risk of potential liver toxicity was low.