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

doi:10.1021/acs.jmedchem.3c00832

科研成果详情

题名	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
作者	Liao, Jing1,2,3; Yang, Jun1; Li, Xiaobo1; Hu, Chenghong1; Zhu, Weiwei1; Zhou, Ying1; Zou, Yu1; Guo, Mi1; Chen, Zhichao 1; Li, Xiang1; Dai, Jintian 3; Xu, Yuye 3; Zheng, Zhiwei1,4; Chen, Pan1,4; Cho, Won-Jea 4; Liang, Guang1,2,3; Tang, Qidong1,3
发表日期	2023-08-29
发表期刊	Journal of medicinal chemistry 影响因子和分区
语种	英语
原始文献类型	Journal Article
其他关键词	ANTIINFLAMMATORY AGENTS ; DERIVATIVES ; DESIGN ; POTENT ; ALPHA ; LPS
摘要	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
资助项目	Zhejiang Provincial Key Scientific Project[2021C03041];Wenzhou Medical University[QTJ21013];National Natural Science Funding of China[21961142009,82273791];Thailand Research Fund[DBG6280006];University of Chinese Academy of Sciences[WIUCASQD2020016];
出版者	AMER CHEMICAL SOC
ISSN	0022-2623
EISSN	1520-4804
卷号	66 期号:17 页码:12304-12323
DOI	10.1021/acs.jmedchem.3c00832
页数	20
WOS类目	Chemistry, Medicinal
WOS研究方向	Pharmacology & Pharmacy
WOS记录号	WOS:001190512100001
收录类别	PUBMED ; SCOPUS ; SCIE
在线发表日期	2023-08
URL	查看原文
PubMed ID	37643372
SCOPUSEID	2-s2.0-85171309534
自科自定义期刊分类	T3(B)类
通讯作者地址	[Liang, Guang]Chemical Biology Research Center,School of Pharmaceutical Sciences,Wenzhou Medical University,Wenzhou,325035,China ; [Tang, Qidong]Chemical Biology Research Center,School of Pharmaceutical Sciences,Wenzhou Medical University,Wenzhou,325035,China
Scopus学科分类	Molecular Medicine;Drug Discovery
TOP期刊	TOP期刊
引用统计
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/182528
专题	药学院（分析测试中心）药学院（分析测试中心）_生物有机与药物化学研究中心
通讯作者	Liang, Guang; Tang, Qidong
作者单位	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,South Korea
第一作者单位	药学院（分析测试中心）; 生物有机与药物化学研究中心
通讯作者单位	药学院（分析测试中心）; 生物有机与药物化学研究中心
第一作者的第一单位	药学院（分析测试中心）
推荐引用方式 GB/T 7714	Liao, Jing,Yang, Jun,Li, Xiaobo,et al. 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]. Journal of medicinal chemistry,2023,66(17):12304-12323.
APA	Liao, Jing., Yang, Jun., Li, Xiaobo., Hu, Chenghong., Zhu, Weiwei., ... & Tang, Qidong. (2023). 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, 66(17), 12304-12323.
MLA	Liao, Jing,et al."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 66.17(2023):12304-12323.