Discovery of 4‑Piperazine Isoquinoline Derivatives as Potent and Brain-Permeable Tau Prion Inhibitors with CDK8 Activity
- 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
- et al.
Published Web Location
https://pubs.acs.org/doi/10.1021/acsmedchemlett.9b00480Abstract
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.
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