Alzheimer’s disease (AD) is a progressive neurodegenerative disorder known to have notable symptoms like short term memory loss otherwise referred to as dementia. Abnormal hyperphosphorylation (P-tau) of the tau protein leads to the aggregation of amyloid plaques which is the hallmark of AD and several other neurodegenerative disorders. Casein kinase 1δ (CK1d) and casein kinase 1ε (CK1e) are the two isozymes expressed in the brain among the eight known isozymes that belong to Casein kinase 1 family. CK1δ plays a critical role in AD through phosphorylation of the tau protein (associated with microtubules) which precedes neuritic lesion formation, involving CK1δ in the tau fibrillization reaction pathway. CK1δ has been reported to be associated with pathological accumulation of tau in several neurodegenerative diseases including AD, Down syndrome, progressive supranuclear palsy, and Parkinsonism dementia complex of Guam. Inhibition of CK1δ has been shown to reduce fibrillar lesions and inhibit Aβ production. Our recent studies on quinones as kinase inhibitors revealed one such compound that pharmacologically inhibited CK1δ and Pim1 kinase preferentially over CK1γ2 and 98 other human protein kinases. We have identified a few more potent inhibitors in addition to the existing compounds, and these compounds were synthesized and preliminary in-vitro CK1δ kinase inhibition assay have shown a few compounds with good potency. Herein, we describe the synthesis and bioassay results of our study.

Development of novel casein kinase 1d inhibitors for treatment of Alzheimer's disease

255th National Meeting (2018)

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