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.

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