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

  • ACS Med Chem Lett. 2020 Jan 30;11(2):127-132. doi: 10.1021/acsmedchemlett.9b00480.
Jean-Marc M Grandjean  1 ,  Alexander Y Jiu  1 ,  John W West  1 ,  Atsushi Aoyagi  2 ,  Daniel G Droege  1 ,  Manuel Elepano  1 ,  Makoto Hirasawa  2 ,  Masakazu Hirouchi  2 ,  Ryo Murakami  2 ,  Joanne Lee  1 ,  Koji Sasaki  2 ,  Shimpei Hirano  2 ,  Takao Ohyama  2 ,  Benjamin C Tang  1 ,  Roy J Vaz  1 ,  Masahiro Inoue  2 ,  Steven H Olson  1 ,  Stanley B Prusiner  1 ,  Jay Conrad  1 ,  Nick A Paras  1
Affiliations
  • 1. Institute for Neurodegenerative Diseases (IND), UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, California 94518, United States.
  • 2. R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
PMID: 32071678 DOI: 10.1021/acsmedchemlett.9b00480
Abstract

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.