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Discovery of 4-Piperazine Isoquinoline Derivatives as Potent and Brain-Permeable Tau Prion Inhibitors with CDK8 Activity.

  • Author(s): 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.

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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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