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<p>ROCK inhibitors can inhibit IL-1β and NLRP3, and their therapeutic potential for osteoarthritis and rheumatoid arthritis has been confirmed, but their impact on gouty arthritis has not been reported yet. By hybridization the structure of Edaravone, a series of ROCK inhibitors with pyrazolone scaffold were designed and synthesized. RM-04 has acceptable selective ROCK2 inhibitory activity with an IC<sub>50</sub> of 4.62 µM, and its IC<sub>50</sub> values for scavenging DPPH<sup>•</sup> and ABTS<sup>•+</sup> are 16.72 µM and 23.15 µM, respectively, which is equivalent to that of Edaravone. Furthermore, RM-04 exhibits good pharmacokinetic properties and good safety in vivo. Meanwhile, in sodium urate-induced acute gout model, RM-04 at a dose of 5&#xa0;mg/kg exhibited the alleviating effect approximately equivalent to that of Celecoxib, indicating that ROCKs inhibitors with antioxidation activity could reduce the damage caused by gouty arthritis.</p> Graphical abstract <p></p>

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Discovery of selective ROCK2 inhibitors with free radical scavenging ability for the treatment of gouty arthritis

  • 期刊论文

  • 发表日期：

    2025年1月23日

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  • Ruolin Cao,
  • Chuqiao Song,
  • Zhe Wang,
  • Bingqing Lv,
  • Wei Xiao,
  • Guoliang Chen,
  • Xuefei Bao

摘要

ROCK inhibitors can inhibit IL-1β and NLRP3, and their therapeutic potential for osteoarthritis and rheumatoid arthritis has been confirmed, but their impact on gouty arthritis has not been reported yet. By hybridization the structure of Edaravone, a series of ROCK inhibitors with pyrazolone scaffold were designed and synthesized. RM-04 has acceptable selective ROCK2 inhibitory activity with an IC50 of 4.62 µM, and its IC50 values for scavenging DPPH• and ABTS•+ are 16.72 µM and 23.15 µM, respectively, which is equivalent to that of Edaravone. Furthermore, RM-04 exhibits good pharmacokinetic properties and good safety in vivo. Meanwhile, in sodium urate-induced acute gout model, RM-04 at a dose of 5 mg/kg exhibited the alleviating effect approximately equivalent to that of Celecoxib, indicating that ROCKs inhibitors with antioxidation activity could reduce the damage caused by gouty arthritis.

Graphical abstract