期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 238, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2022.114423
关键词
Sepsis; BRD4 inhibitor; Bromodomain; BET
资金
- National Natural Science Foundation of China [82173680, 81930100]
- Priority Academic Program Development of Jiangsu Higher Education Institutions
- Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University [SKLNMZZ202003]
- National Innovation and Entrepreneurship Training Program for Undergraduate [202210316128]
- Qing Lan Project of Jiangsu Province
- Young Elite Scientists Sponsorship Program by CAST (China) [YESS20180146]
Sepsis is a global health problem and BRD4 inhibitor 27 could be a potential candidate for sepsis treatment.
Sepsis has long been a major health problem worldwide. It threatens the lives of hospitalized patients and has been one of the leading causes of death in hospitalized patients over the past decades. BRD4 has been regarded as a potential target for sepsis therapy, for its critical role in the transcriptional expression of NF-kappa B pathway-dependent inflammatory factors. In this study, compound 1 was obtained through virtual screening, and candidate compound 27 was obtained through several rounds of iterative SAR analysis. 27 decreased LPS-induced NO production and expression of the pro-inflammatory factors IL-6, IL-1 beta and TNF-alpha. In vivo, 27 effectively protected mice from LPS-induced sepsis, increased survival rate and decreased the level of pro-inflammatory factors in serum. Collectively, we reported here 27, a BRD4 inhibitor with a new scaffold, as a potential candidate for the treatment of sepsis.
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