Wenfeng Ye, Mingchao He, Gaofeng Lin, Li Shao, Jiajia Mo, Yan Zhao, Xiaodong Ma, Qinlong Xu, Zhaoxing Chu
{"title":"通过封闭代谢位点发现新的苯溴马龙衍生物作为有效的人类尿酸转运蛋白1 （URAT1）抑制剂","authors":"Wenfeng Ye, Mingchao He, Gaofeng Lin, Li Shao, Jiajia Mo, Yan Zhao, Xiaodong Ma, Qinlong Xu, Zhaoxing Chu","doi":"10.1007/s00044-025-03389-2","DOIUrl":null,"url":null,"abstract":"<div><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><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 4","pages":"929 - 943"},"PeriodicalIF":2.6000,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Discovery of novel benzbromarone derivatives via the closed metabolic site as potent human uric acid transporter 1 (URAT1) inhibitors\",\"authors\":\"Wenfeng Ye, Mingchao He, Gaofeng Lin, Li Shao, Jiajia Mo, Yan Zhao, Xiaodong Ma, Qinlong Xu, Zhaoxing Chu\",\"doi\":\"10.1007/s00044-025-03389-2\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><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><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>\",\"PeriodicalId\":699,\"journal\":{\"name\":\"Medicinal Chemistry Research\",\"volume\":\"34 4\",\"pages\":\"929 - 943\"},\"PeriodicalIF\":2.6000,\"publicationDate\":\"2025-02-28\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Medicinal Chemistry Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://link.springer.com/article/10.1007/s00044-025-03389-2\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Medicinal Chemistry Research","FirstCategoryId":"3","ListUrlMain":"https://link.springer.com/article/10.1007/s00044-025-03389-2","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Discovery of novel benzbromarone derivatives via the closed metabolic site as potent human uric acid transporter 1 (URAT1) inhibitors
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.
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.
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