Discovery of the Diphenyl 6-Oxo-1,6-dihydropyridazine-3-carboxylate/carboxamide Analogue J27 for the Treatment of Acute Lung Injury and Sepsis by Targeting JNK2 and Inhibiting the JNK2-NF-κB/MAPK Pathway,Journal of Medicinal Chemistry

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Discovery of the Diphenyl 6-Oxo-1,6-dihydropyridazine-3-carboxylate/carboxamide Analogue J27 for the Treatment of Acute Lung Injury and Sepsis by Targeting JNK2 and Inhibiting the JNK2-NF-κB/MAPK Pathway
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-08-29 , DOI: 10.1021/acs.jmedchem.3c00832
Jing Liao _{1,

2,

3} , Jun Yang ₁ , Xiaobo Li ₁ , Chenghong Hu ₁ , Weiwei Zhu ₁ , Ying Zhou ₁ , Yu Zou ₁ , Mi Guo ₁ , Zhichao Chen ₁ , Xiang Li ₁ , Jintian Dai ₃ , Yuye Xu ₃ , Zhiwei Zheng _{1,

4} , Pan Chen _{1,

4} , Won-Jea Cho ₄ , Guang Liang _{1,

2,

3} , Qidong Tang _{1,

3}

Affiliation

Acute lung injury (ALI) and sepsis are both serious and complex conditions associated with high mortality, yet there are no effective treatments. Herein, we designed and synthesized a series of diphenyl 6-oxo-1,6-dihydropyridazine-3-carboxylate/carboxamide analogues exhibiting anti-inflammatory activity. The optimal compound J27 decreased the release of TNF-α and IL-6 in mouse and human cells J774A.1 and THP-1 (IL-6 IC₅₀ = 0.22 μM) through the NF-κB/MAPK pathway. J27 demonstrated remarkable protection against ALI and sepsis in vivo and exhibited good safety in subacute toxicity experiments. Pharmacokinetic study indicated that J27 had good bioavailability (30.74%). To our surprise, J27 could target JNK2 with a totally new molecular skeleton compared with the only few JNK2 inhibitors reported. Moreover, there is no report that JNK2 inhibitors could apply for ALI and sepsis. Therefore, this work provides a new lead structure for the study of JNK2 inhibitors and a new target of JNK2 to treat ALI and sepsis.

中文翻译：

发现二苯基 6-Oxo-1,6-二氢哒嗪-3-羧酸酯/甲酰胺类似物 J27 通过靶向 JNK2 并抑制 JNK2-NF-κB/MAPK 通路治疗急性肺损伤和脓毒症

急性肺损伤（ALI）和脓毒症都是严重且复杂的疾病，死亡率较高，但尚无有效的治疗方法。在此，我们设计并合成了一系列具有抗炎活性的二苯基6-氧代-1,6-二氢哒嗪-3-羧酸酯/甲酰胺类似物。最佳化合物J27通过 NF-κB/MAPK 途径减少小鼠和人类细胞 J774A.1 和 THP-1 中 TNF-α 和 IL-6 的释放 (IL-6 IC _{50 = 0.22 μM)。}J27在体内表现出对ALI和败血症的显着保护作用，并在亚急性毒性实验中表现出良好的安全性。药代动力学研究表明J27具有良好的生物利用度（30.74%）。令我们惊讶的是，与报道的少数 JNK2 抑制剂相比，J27能够以全新的分子骨架靶向 JNK2。此外，尚无JNK2抑制剂可用于ALI和脓毒症治疗的报道。因此，该工作为JNK2抑制剂的研究提供了新的先导结构，也为JNK2治疗ALI和脓毒症提供了新的靶点。

更新日期：2023-08-29

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