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 , 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 . Structure-activity relationship studies identified compound as the most potent, with a K of 42.2 nM against Keap1. Furthermore, compound 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 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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发现新型 5-苯基-1H-吡咯-2-羧酸作为 Keap1-Nrf2 抑制剂用于治疗急性肺损伤


氧化应激与急性肺损伤（ALI）和脑缺血/再灌注（I/R）损伤密切相关。 Keap1（Kelch 样 ECH 相关蛋白 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，具有巨大的治疗潜力两种疾病。在我们的实验室中，我们最初筛选了化合物库并鉴定了化合物 ，该化合物的 Keap1 解离常数为 5090 nM。为了增强其结合亲和力，我们通过化合物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。构效关系研究发现该化合物是最有效的，针对 Keap1 的 K 值为 42.2 nM。此外，该化合物对 BEAS-2B 细胞中 LPS 诱导的损伤具有显着的保护作用，并促进 Nrf2 核转位。随后，我们研究了其在 ALI 损伤小鼠模型中的治疗效果。 15 mg/kg 剂量的化合物可有效缓解 ALI 损伤的症状。此外，它还促进 Nrf2 易位到细胞核，增加 Nrf2 水平，并上调受影响组织中 HO-1 和 NQO1 的表达。