2. Academic Validation
  3. Discovery of novel benzomorpholine derivatives as potent URAT1 inhibitors with hypouricemic effects

Discovery of novel benzomorpholine derivatives as potent URAT1 inhibitors with hypouricemic effects

  • Bioorg Med Chem Lett. 2025 Jul 14:128:130342. doi: 10.1016/j.bmcl.2025.130342.
Yongcheng Wang 1,  Lei Zhang 1,  Mengjie Shao 1,  Xianxin Hou 1,  Ying Yang 1,  Yifan Yang 1,  Fei Ye 2,  Xuechen Li 3,  Zhiyan Xiao 4
Affiliations

Affiliations

  • 1 Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
  • 2 Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
  • 3 Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address: xli@imm.ac.cn.
  • 4 Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; State Key Laboratory of Digestive Health, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address: xiaoz@imm.ac.cn.
PMID: 40669671 DOI: 10.1016/j.bmcl.2025.130342
Abstract

Urate transporter 1 (URAT1) is a clinically validated therapeutic target for hyperuricemia and gout. To obtain structurally novel URAT1 inhibitors, a series of benzomorpholine derivatives were designed by adopting a pharmacophore guided molecular hybridization strategy. Most compounds potently inhibit the human URAT1 in HEK293 cells, and the most active compound 7 exhibited an IC50 of 0.72 μM, which was much more potent than Lesinurad and comparable to Benzbromarone. The possible interaction mode of compound 7 with URAT1 was revealed by molecular modeling. Cell viability assays indicated that compound 7 was less cytotoxic than Benzbromarone in Hep-G2 cells. The urate-lowering effects of compounds 1 and 7 were confirmed in two different hyperuricemia mouse models, and no obvious toxicity was observed in the treated mice. The results provide new chemical prototypes for urate-lowering drug discovery targeting URAT1.

Keywords

Benzomorpholine scaffold; Gout; Hyperuricemia; Hypouricemic efficacy; URAT1 inhibitor.

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