药理学
吩噻嗪
药代动力学
化学
冲程(发动机)
程序性细胞死亡
体外
铅化合物
缺血性中风
HT1080型
细胞凋亡
药品
生物化学
细胞
医学
缺血
内科学
工程类
机械工程
作者
Wei Yang,Xiaolong Liu,Chunli Song,Songbai Ji,Jianhong Yang,Yang Liu,Jianxin You,Jie Zhang,Shenzhen Huang,Wei Cheng,Zhenhua Shao,Linli Li,Shengyong Yang
标识
DOI:10.1016/j.ejmech.2020.112842
摘要
Ferroptosis is a new type of programmed cell death discovered recently and has been demonstrated to be involved in a number of human diseases such as ischemic stroke. Ferroptosis inhibitors are expected to have potential to treat these diseases. Herein, we report the identification of promethazine derivatives as a new type of ferroptosis inhibitors. Structure-activity relationship (SAR) analyses led to the discovery of the most potent compound 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine (51), which showed an EC50 (half maximal effective concentration) value of 0.0005 μM in the erastin-induced HT1080 cell ferroptosis model. In the MCAO (middle cerebral artery occlusion) ischemic stroke model, 51 presented an excellent therapeutic effect. This compound also displayed favorable pharmacokinetic properties, in particular, a good ability to permeate the blood-brain barrier. Overall, 51 could be a promising lead compound for the treatment of ferroptosis related diseases and deserves further investigations.
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