Synthesis and Pharmacological Evaluation of New N-Sulfonylureas as NLRP3 Inflammasome Inhibitors: Identification of a Hit Compound to Treat Gout,Journal of Medicinal Chemistry

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Synthesis and Pharmacological Evaluation of New N-Sulfonylureas as NLRP3 Inflammasome Inhibitors: Identification of a Hit Compound to Treat Gout
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-04-11 , DOI: 10.1021/acs.jmedchem.2c00149
Paloma Narros-Fernández _{1,

2,

3} , Mourad Chioua ₄ , Sonia A Petcu ₄ , Daniel Diez-Iriepa _{4,

5} , Laura Cerrada-Gálvez _{1,

2,

3} , Céline Decouty-Pérez _{1,

2,

3} , Alejandra Palomino-Antolín _{1,

2,

3} , Eva Ramos ₆ , Víctor Farré-Alins _{1,

2,

3} , Ana Belén López-Rodríguez _{1,

2,

3} , Alejandro Romero ₆ , José Marco-Contelles ₄ , Javier Egea _{1,

2,

3}

Affiliation

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.

中文翻译：

作为 NLRP3 炎性体抑制剂的新型 N-磺脲类药物的合成和药理学评价：治疗痛风的有效化合物的鉴定

NLRP3 参与了几种炎症性疾病的病理生理学。因此，目前对临床开发新的 NLRP3 炎症小体抑制剂来治疗这些疾病具有很高的兴趣。通过替换先前描述的NLRP3抑制剂MCC950的六氢茚满部分获得新型N-磺酰脲。这些新的衍生物在体外抑制 IL-1β 释放方面表现出中到高效能。化合物4b的效果最大，与 MCC950 相似。此外，化合物4b能够减少 caspase-1 的活化、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4b的安全性和 AML12 肝细胞的体外研究证实没有毒理学作用。最后，我们评估了化合物 4b 的体内抗炎特性，在痛风的体内小鼠模型中，化合物4b在 3 和 10 mg/kg (ip) 时显示出显着的抗炎作用并降低了机械痛觉过敏。

更新日期：2022-04-11

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