Molecular Neuroinflammation and Neuronal Plasticity Research Laboratory, Hospital Universitario Santa Cristina, Calle Maestro Vives 2, 28009 Madrid, Spain.
IIS-Hospital Universitario de La Princesa, 28006 Madrid, Spain.
J Med Chem. 2022 Apr 28;65(8):6250-6260. doi: 10.1021/acs.jmedchem.2c00149. Epub 2022 Apr 11.
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 -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 , which was similar to MCC950. Moreover, compound 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 , and in vitro studies in AML12 hepatic cells confirmed the absence of toxicological effects. Finally, we evaluated in vivo anti-inflammatory properties of compound , 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学。因此，目前人们对开发新的 NLRP3 炎性小体小分子抑制剂来治疗这些疾病非常感兴趣。新型 - 磺酰脲类化合物是通过取代先前描述的 NLRP3 抑制剂 MCC950 的六氢茚并部分得到的。这些新的衍生物在体外抑制 IL-1β释放方面表现出中等至高的效力。观察到化合物 的效果最大，与 MCC950 相似。此外，化合物 能够减少 caspase-1 的激活、ASC 的寡聚化，从而减少 IL-1β的加工。额外的计算机预测证实了化合物 的安全性，在 AML12 肝细胞中的体外研究证实了其没有毒性作用。最后，我们评估了化合物 在体内的抗炎特性，结果表明在痛风的体内小鼠模型中，化合物 在 3 和 10mg/kg（ip）剂量下具有显著的抗炎作用，并减轻了机械性痛觉过敏。
