2. Academic Validation
  3. Benzoheterocyclic analogues of dotinurad as orally efficacious human urate transporter 1 inhibitors: Design, synthesis, structure-activity relationships, and pharmacokinetic studies

Benzoheterocyclic analogues of dotinurad as orally efficacious human urate transporter 1 inhibitors: Design, synthesis, structure-activity relationships, and pharmacokinetic studies

  • Eur J Med Chem. 2026 Feb 5:303:118459. doi: 10.1016/j.ejmech.2025.118459.
Linjian Zhang 1,  Kaijun Su 1,  Haoshu Zhang 1,  Guowei Zhang 2,  Jian Zhou 1,  Jiaqi Liang 1,  Xiang Li 3,  Xiaojin Zhang 4
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 211198, China; Department of Chemistry, School of Science, China Pharmaceutical University, Nanjing, 211198, China.
  • 2 Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 211198, China; Department of Pharmaceutical Engineering, China Pharmaceutical University, Nanjing, 211198, China.
  • 3 Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 211198, China; Department of Pharmaceutical Engineering, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: lixiang@cpu.edu.cn.
  • 4 Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 211198, China; Department of Chemistry, School of Science, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: zxj@cpu.edu.cn.
PMID: 41353866 DOI: 10.1016/j.ejmech.2025.118459
Abstract

A series of benzoheterocyclic analogues of Dotinurad were designed and synthesized as URAT1 inhibitors via bioisosterism and linker modification strategies. Among the 19 synthesized derivatives, compounds 9, 13, and 14 (bearing benzimidazole, benzotetrahydropyrrole, and benzo[b]thiazine 1,1-dioxide scaffolds, respectively) exhibited acceptable inhibitory potency (IC50: 69.81-441.51 nM), favorable metabolic stability, and improved pharmacokinetic profiles compared to Dotinurad. Notably, despite showing weaker in vitro URAT1 inhibition than the Dotinurad, these three candidates demonstrated significantly superior uricosuric activity in hyperuricemic rats. Mechanistic investigation revealed that the substantial excretion of unchanged prototype compounds into the urine ensured a high local concentration within the renal tubule lumen, which effectively compensated for their moderate in vitro affinity. These findings validated the design strategy and highlighted compounds 9, 13, and 14 as promising candidates for hyperuricemia treatment.

Keywords

Benzohetercyclic analogues; Hyperuricemia; URAT1 inhibitors.

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