Oxidative stress is intricately linked to acute lung injury (ALI) and cerebral ischemic/reperfusion (I/R) injury. The Keap1 (Kelch-like ECH-Associating protein 1)-Nrf2 (nuclear factor erythroid 2-related factor 2)-ARE (antioxidant response element) signaling pathway, recognized as a crucial regulatory mechanism in oxidative stress, holds immense potential for the treatment of both diseases. In our laboratory, we initially screened a compound library and identified compound 3, which exhibited a dissociation constant of 5090 nM for Keap1. To enhance its binding affinity, we developed a novel 5-phenyl-1H-pyrrole-2-carboxylic acid Keap1-Nrf2 inhibitor through scaffold hopping from compound 3. Structure-activity relationship studies identified compound 19 as the most potent, with a KD2 of 42.2 nM against Keap1. Furthermore, compound 19 showed significant protection against LPS-induced injury in BEAS-2B cells and promoted Nrf2 nuclear translocation. Subsequently, we investigated its therapeutic effects in mouse models of ALI injury. Compound 19 effectively alleviated symptoms at doses of 15 mg/kg for ALI injury. Additionally, it facilitated Nrf2 translocation to the nucleus, increased Nrf2 levels, and upregulated the expression of HO-1 and NQO1 in affected tissues.

中文翻译：

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新型 5-苯基-1H-吡咯-2-羧酸作为 Keap1-Nrf2 抑制剂治疗急性肺损伤的发现


氧化应激与急性肺损伤 （ALI） 和脑缺血/再灌注 （I/R） 损伤有着错综复杂的联系。Keap1 （Kelch 样 ECH-关联蛋白 1）-Nrf2 （核因子红细胞 2 相关因子 2）-ARE （抗氧化反应元件） 信号通路，被认为是氧化应激的关键调节机制，在治疗这两种疾病方面具有巨大潜力。在我们的实验室中，我们最初筛选了一个化合物库并鉴定了化合物 3，该化合物对 Keap1 的解离常数为 5090 nM。为了增强其结合亲和力，我们通过化合物 3 的支架跳跃开发了一种新型 5-苯基-1H-吡咯-2-羧酸 Keap1-Nrf2 抑制剂。构效关系研究确定化合物 19 最有效，对 Keap1 的 KD2 为 42.2 nM。此外，化合物 19 在 BEAS-2B 细胞中显示出对 LPS 诱导损伤的显着保护，并促进 Nrf2 核转位。随后，我们在 ALI 损伤小鼠模型中研究了其治疗效果。化合物 19 在 15 mg/kg 剂量下有效缓解了 ALI 损伤的症状。此外，它还促进了 Nrf2 易位到细胞核，增加了 Nrf2 水平，并上调了受影响组织中 HO-1 和 NQO1 的表达。