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

IF 2.6 4区医学 Q3 CHEMISTRY, MEDICINAL

Medicinal Chemistry Research Pub Date : 2025-02-28 DOI:10.1007/s00044-025-03389-2

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

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Abstract

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.

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来源期刊

Medicinal Chemistry Research 医学-医药化学

CiteScore

4.70

自引率

3.80%

发文量

162

审稿时长

5.0 months

期刊介绍： Medicinal Chemistry Research (MCRE) publishes papers on a wide range of topics, favoring research with significant, new, and up-to-date information. Although the journal has a demanding peer review process, MCRE still boasts rapid publication, due in part, to the length of the submissions. The journal publishes significant research on various topics, many of which emphasize the structure-activity relationships of molecular biology.