ACS medicinal chemistry letters · 2020
Discovery of 4-Piperazine Isoquinoline Derivatives as Potent and Brain-Permeable Tau Prion Inhibitors with CDK8 Activity.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Grandjean Jean-Marc M, Jiu Alexander Y, West John W, Aoyagi Atsushi, Droege Daniel G, Elepano Manuel, Hirasawa Makoto, Hirouchi Masakazu, Murakami Ryo, Lee Joanne, Sasaki Koji, Hirano Shimpei, Ohyama Takao, Tang Benjamin C, Vaz Roy J, Inoue Masahiro, Olson Steven H, Prusiner Stanley B, Conrad Jay, Paras Nick A
Аннотация
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 (1) was identified as a hit with an EC50 value of 390 nM and 0.04 K p,uu. Analogs were synthesized using a hypothesis-based approach to improve potency and in vivo brain penetration resulting in compound 25 (EC50 = 15 nM; K p,uu = 0.63). We investigated the mechanism of action of this series and found that a small set of active compounds were also CDK8 inhibitors.