1781486-94-9Relevant articles and documents
Discovery of 4-Piperazine Isoquinoline Derivatives as Potent and Brain-Permeable Tau Prion Inhibitors with CDK8 Activity
Aoyagi, Atsushi,Conrad, Jay,Droege, Daniel G.,Elepano, Manuel,Grandjean, Jean-Marc M.,Hirano, Shimpei,Hirasawa, Makoto,Hirouchi, Masakazu,Inoue, Masahiro,Jiu, Alexander Y.,Lee, Joanne,Murakami, Ryo,Ohyama, Takao,Olson, Steven H.,Paras, Nick A.,Prusiner, Stanley B.,Sasaki, Koji,Tang, Benjamin C.,Vaz, Roy J.,West, John W.
, (2020)
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 Kp,uu. Analogs were synthesized using a hypothesis-based approach to improve potency and in vivo brain penetration resulting in compound 25 (EC50 = 15 nM; Kp,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.
