Alzheimer's disease (AD) remains an incurable neurodegenerative condition that poses a threat to humanity. Immune signaling in the brain, particularly the NLR family pyrin domain containing 3 (NLRP3), is currently targeted for AD treatment. Based on the crystal structure of the NACHT domain of NLRP3 and its renowned inhibitor MCC950, we designed and synthesized nineteen sulfonylurea compounds and evaluated their capacity to inhibit caspase-1 and interleukin-1β (IL-1β). Of these, nine were selected for measuring their IC for caspase-1 and cytotoxicity analysis. Finally, three compounds were chosen to assess their inhibitory effect on IL-1β in mice. The results showed that compound had a superior ability to reduce IL-1β levels in the brain compared to MCC950 at a lower dosing concentration, indicating that has the potential to penetrate the blood–brain barrier (BBB) and inhibit inflammation both and . Docking studies of compound on NLRP3 revealed a binding mode similar to MCC950. These findings suggest that compound holds promise as an NLRP3 inhibitor for AD treatment.

中文翻译：

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基于结构的设计和合成磺酰脲类药物作为阿尔茨海默病的新型 NLRP3 抑制剂

阿尔茨海默病（AD）仍然是一种无法治愈的神经退行性疾病，对人类构成威胁。大脑中的免疫信号传导，特别是 NLR 家族吡啶结构域 3 (NLRP3)，目前是 AD 治疗的目标。基于NLRP3的NACHT结构域及其著名抑制剂MCC950的晶体结构，我们设计并合成了19种磺酰脲类化合物，并评估了它们抑制caspase-1和白细胞介素1β（IL-1β）的能力。其中，选择了 9 个来测量 caspase-1 的 IC 值和细胞毒性分析。最后，选择三种化合物来评估它们对小鼠 IL-1β 的抑制作用。结果表明，与较低剂量浓度的 MCC950 相比，该化合物具有卓越的降低大脑中 IL-1β 水平的能力，表明该化合物具有穿透血脑屏障 (BBB) 并抑制炎症的潜力。化合物与 NLRP3 的对接研究揭示了与 MCC950 类似的结合模式。这些发现表明该化合物有望作为 NLRP3 抑制剂用于 AD 治疗。