Discovery of Novel 2,3-Dihydro-1H-indene-5-sulfonamide NLRP3 Inflammasome Inhibitors Targeting Colon as a Potential Therapy for Colitis,Journal of Medicinal Chemistry

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Discovery of Novel 2,3-Dihydro-1H-indene-5-sulfonamide NLRP3 Inflammasome Inhibitors Targeting Colon as a Potential Therapy for Colitis
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-11-29 , DOI: 10.1021/acs.jmedchem.3c01511
Simin Sun ₁ , Zhuoyue Li _{1,

2} , Chao Huang ₁ , Jinyu Liu ₁ , Qixin Yu ₃ , Xiaolin Jiang _{1,

2} , Kairui Yue ₁ , Jianchun Zhao ₁ , Tongqiang Xu ₃ , Yankai Liu ₁ , Xiaoyang Li _{1,

2,

3} , Chong Qin _{1,

2,

3} , Yuqi Jiang _{1,

2,

3}

Affiliation

The NLRP3 inflammasome is a multiprotein complex that plays a crucial role in the pathophysiology of multiple inflammation-related diseases. In this study, we designed and synthesized a series of novel 2,3-dihydro-1H-indene-5-sulfonamide analogues as NLRP3 inflammasome inhibitors, and then identified compound 15z as a potent and specific inhibitor (IC₅₀: 0.13 μM) with low toxicity. Mechanistic studies indicate that 15z binds directly to NLRP3 protein (K_D: 102.7 nM), blocking the assembly and activation of the NLRP3 inflammasome and effectively inhibiting cell pyroptosis. Given the notable distribution of 15z in the colon, the DSS-induced colitis model was employed to evaluate its in vivo effectiveness. 15z significantly impacted NLRP3 inflammasome activation and relieved inflammatory bowel disease symptoms in this model. Acute and subacute toxicity studies suggested that 15z has a favorable safety profile. Our results indicate that 15z has great potential to be further developed as a candidate for the treatment of inflammatory bowel disease.

中文翻译：

发现针对结肠的新型 2,3-二氢-1H-茚-5-磺酰胺 NLRP3 炎症小体抑制剂，作为结肠炎的潜在疗法

NLRP3炎症小体是一种多蛋白复合物，在多种炎症相关疾病的病理生理学中发挥着至关重要的作用。在本研究中，我们设计并合成了一系列新型2,3-二氢-1H-茚-5-磺酰胺类似物作为NLRP3炎症小体抑制剂，并鉴定出化合物15z是一种有效且特异性的抑制剂（IC ₅₀ ：0.13 μM）毒性低。机理研究表明， 15z直接与NLRP3蛋白（ K _D ：102.7 nM）结合，阻断NLRP3炎症小体的组装和激活，有效抑制细胞焦亡。鉴于15z在结肠中的显着分布，采用 DSS 诱导的结肠炎模型来评估其体内有效性。在此模型中， 15z显着影响 NLRP3 炎症小体激活并缓解炎症性肠病症状。急性和亚急性毒性研究表明15z具有良好的安全性。我们的结果表明， 15z作为治疗炎症性肠病的候选药物具有进一步开发的巨大潜力。

更新日期：2023-11-29

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