Work

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

Year: 2020

Type: article

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 EC 50 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 (EC 50 = 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.

Source: ACS Medicinal Chemistry Letters

DOI: 10.1021/acsmedchemlett.9b00480