Scholarlink

<p>Hyperuricemia arises from disrupted uric acid metabolism, where xanthine oxidoreductase (XOR) and uric acid transporter 1 (URAT1) serve as key therapeutic targets for uric acid production and reabsorption, respectively. While current single-target drugs inhibit either XOR or URAT1, dual-target strategies combining both inhibitors are clinically promising. In this research, fragment-based drug design coupled with virtual screening was employed to obtain hit compounds <b>A1</b>-<b>4</b>. Among them, <b>A4</b> exhibited strong inhibitory effects on URAT1 (IC<sub>50</sub> = 33.10 ± 7.82 μM), comparable to benzbromarone (IC<sub>50</sub> = 21.67 ± 7.31 μM). Additionally, <b>A4</b> showed a certain degree of inhibition on XOR, with an IC<sub>50</sub> value of 20.73 ± 2.19 μM, significantly weaker than allopurinol (IC<sub>50</sub> = 1.43 ± 0.02 μM). Thus, the first round of optimization from <b>A4</b> focused on enhancing the inhibitory activity against XOR. By molecular docking studies of <b>A4</b> with XOR, compounds <b>B1</b>-<b>13</b> were designed and synthsized. Among those compounds, <b>B8</b> showed the best inhibitory activity against XOR (IC<sub>50</sub> = 10.14 ± 1.43 μM), approximately twice enhancement as compared to that of <b>A4</b>. Unfortunately, the inhibitory activity of <b>B</b> series compounds on URAT1 (IC<sub>50</sub> = 10.14 ± 1.43 μM) were significantly reduced compared to <b>A4</b>. By the structure-activity relationships analysis, it was considered that further optimization studies can be conducted based on <b>B8</b> and <b>A4</b>.</p><p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

New structural scaffold discovery via fragment-based drug design: Hydroxymethyl indazole derivatives as XOR/URAT1 dual inhibitors

  • 期刊论文

  • 发表日期：

    2025年11月26日

查看全文
  • Haiqing Ma,
  • Hongming Chen,
  • Lei Zhang,
  • Jing Li

摘要

Hyperuricemia arises from disrupted uric acid metabolism, where xanthine oxidoreductase (XOR) and uric acid transporter 1 (URAT1) serve as key therapeutic targets for uric acid production and reabsorption, respectively. While current single-target drugs inhibit either XOR or URAT1, dual-target strategies combining both inhibitors are clinically promising. In this research, fragment-based drug design coupled with virtual screening was employed to obtain hit compounds A1-4. Among them, A4 exhibited strong inhibitory effects on URAT1 (IC50 = 33.10 ± 7.82 μM), comparable to benzbromarone (IC50 = 21.67 ± 7.31 μM). Additionally, A4 showed a certain degree of inhibition on XOR, with an IC50 value of 20.73 ± 2.19 μM, significantly weaker than allopurinol (IC50 = 1.43 ± 0.02 μM). Thus, the first round of optimization from A4 focused on enhancing the inhibitory activity against XOR. By molecular docking studies of A4 with XOR, compounds B1-13 were designed and synthsized. Among those compounds, B8 showed the best inhibitory activity against XOR (IC50 = 10.14 ± 1.43 μM), approximately twice enhancement as compared to that of A4. Unfortunately, the inhibitory activity of B series compounds on URAT1 (IC50 = 10.14 ± 1.43 μM) were significantly reduced compared to A4. By the structure-activity relationships analysis, it was considered that further optimization studies can be conducted based on B8 and A4.