Synthesis and Pharmacological Evaluation of New N‑Sulfonylureas as NLRP3 Inflammasome Inhibitors: Identification of a Hit Compound to Treat Gout

NLRP3 is involved in the pathophysiology of several inflammatory diseases. Therefore, there is high current interest in the clinical development of new NLRP3 inflammasome small inhibitors to treat these diseases. Novel N-sulfonylureas were obtained by the replacement of the hexahydroindacene moiety of the previously described NLRP3 inhibitor MCC950. These new derivatives show moderate to high potency in inhibiting IL-1β release in vitro. The greatest effect was observed for compound 4b, which was similar to MCC950. Moreover, compound 4b was able to reduce caspase-1 activation, oligomerization of ASC, and therefore, IL-1β processing. Additional in silico predictions confirmed the safety profile of compound 4b, and in vitro studies in AML12 hepatic cells confirmed the absence of toxicological effects. Finally, we evaluated in vivo anti-inflammatory properties of compound 4b, which showed a significant anti-inflammatory effect and reduced mechanical hyperalgesia at 3 and 10 mg/kg (i.p.) in an in vivo mouse model of gout.

NLRP3参与多种炎症性疾病的病理生理过程。因此，当前临床领域对新型NLRP3炎症小体（NLRP3 inflammasome）小分子抑制剂的开发抱有极高关注度，旨在用于治疗上述炎症性疾病。研究人员通过替换此前报道的NLRP3抑制剂MCC950的六氢茚满（hexahydroindacene）结构片段，合成了一系列新型N-磺酰脲类化合物。这些衍生物在体外抑制白细胞介素-1β（IL-1β）释放方面展现出中等到较高的活性。其中化合物4b的抑制效果最为显著，其活性与MCC950相当。此外，化合物4b可抑制半胱天冬酶-1（caspase-1）的活化与ASC的寡聚化，进而阻断IL-1β的成熟加工过程。进一步的虚拟实验（in silico）预测结果证实了化合物4b的安全性谱，而在AML12肝细胞中开展的体外实验则确认其未表现出任何毒性作用。最后，研究人员评估了化合物4b的体内抗炎活性：在痛风小鼠体内模型中，以3 mg/kg和10 mg/kg剂量进行腹腔注射（i.p.）时，化合物4b展现出显著的抗炎效果，并可缓解机械性痛觉超敏。