2. Academic Validation
  3. 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

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

  • J Med Chem. 2023 Sep 14;66(17):12304-12323. 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
Affiliations

Affiliations

  • 1 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
  • 2 School of Pharmacy, Hangzhou Medical College, Hangzhou 311399, China.
  • 3 Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325024, China.
  • 4 College of Pharmacy, Chonnam National University, Gwangju 61186, Korea.
PMID: 37643372 DOI: 10.1021/acs.jmedchem.3c00832
Abstract

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.

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