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

Published on Jan 30, 2020in ACS Medicinal Chemistry Letters4.345
· DOI :10.1021/ACSMEDCHEMLETT.9B00480
Jean-Marc M. Grandjean2
Estimated H-index: 2
(UCSF: University of California, San Francisco),
Alexander Y. Jiu2
Estimated H-index: 2
(UCSF: University of California, San Francisco)
+ 17 AuthorsNick A. Paras10
Estimated H-index: 10
(UCSF: University of California, San Francisco)
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.
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