Discovery of 4-Piperazine Isoquinoline Derivatives as Potent and Brain-Permeable Tau Prion Inhibitors with CDK8 Activity.
ACS medicinal chemistry letters(2020)
摘要
Tau prions feature in the brains of patients suffering from Alzheimer's disease and other tauopathies. For the development of therapeutics that target the replication of tau prions, a high-content, fluorescence-based cell assay was developed. Using this high-content phenotypic screen for nascent tau prion formation, a 4-piperazine isoquinoline compound () was identified as a hit with an EC value of 390 nM and 0.04 . Analogs were synthesized using a hypothesis-based approach to improve potency and brain penetration resulting in compound (EC = 15 nM; = 0.63). We investigated the mechanism of action of this series and found that a small set of active compounds were also CDK8 inhibitors.
更多查看译文
关键词
Tau,neurodegeneration,phenotypic assay,prion,CDK8,brain permeation
AI 理解论文
溯源树
样例
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要