State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
Eur J Med Chem. 2022 Aug 5;238:114423. doi: 10.1016/j.ejmech.2022.114423. Epub 2022 May 8.
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-κB 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-1β and TNF-α. 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.
败血症长期以来一直是全球范围内的一个主要健康问题。它威胁着住院患者的生命，并且在过去几十年中一直是住院患者死亡的主要原因之一。BRD4 被认为是败血症治疗的一个潜在靶点，因为它在 NF-κB 通路依赖性炎症因子的转录表达中起着关键作用。在这项研究中，通过虚拟筛选获得了化合物 1，通过几轮迭代 SAR 分析获得了候选化合物 27。27 减少了 LPS 诱导的 NO 产生和促炎因子 IL-6、IL-1β 和 TNF-α 的表达。在体内，27 有效保护 LPS 诱导的败血症小鼠，提高存活率并降低血清中促炎因子的水平。总之，我们在这里报道了 27，一种具有新骨架的 BRD4 抑制剂，作为治疗败血症的潜在候选药物。
