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

IF 3.8 2区化学 Q2 CHEMISTRY, APPLIED Molecular Diversity Pub Date : 2025-01-23 DOI:10.1007/s11030-024-11054-w

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

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Abstract

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.

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发现具有自由基清除能力的选择性ROCK2抑制剂治疗痛风性关节炎。

ROCK抑制剂可抑制IL-1β和NLRP3，其治疗骨关节炎和类风湿关节炎的潜力已被证实，但其对痛风性关节炎的影响尚未见报道。通过对依达拉奉结构的杂化，设计并合成了一系列以吡唑酮为骨架的ROCK抑制剂。RM-04具有较好的选择性ROCK2抑制活性，IC50值为4.62µM，其清除DPPH•和ABTS•+的IC50值分别为16.72µM和23.15µM，与依达拉奉相当。此外，RM-04具有良好的药动学特性和良好的体内安全性。同时，在尿酸钠诱导的急性痛风模型中，RM-04在5 mg/kg剂量下的缓解效果与塞来昔布大致相当，说明具有抗氧化活性的ROCKs抑制剂可以减轻痛风性关节炎的损伤。

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来源期刊

Molecular Diversity 化学-化学综合

CiteScore

7.30

自引率

7.90%

发文量

219

审稿时长

2.7 months

期刊介绍： Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including: combinatorial chemistry and parallel synthesis; small molecule libraries; microwave synthesis; flow synthesis; fluorous synthesis; diversity oriented synthesis (DOS); nanoreactors; click chemistry; multiplex technologies; fragment- and ligand-based design; structure/function/SAR; computational chemistry and molecular design; chemoinformatics; screening techniques and screening interfaces; analytical and purification methods; robotics, automation and miniaturization; targeted libraries; display libraries; peptides and peptoids; proteins; oligonucleotides; carbohydrates; natural diversity; new methods of library formulation and deconvolution; directed evolution, origin of life and recombination; search techniques, landscapes, random chemistry and more;