Kiyoshi Takayama, Norimasa Morita and Gerhard Müller

Mercachem bv, PO Box 6747, 6503 GE Nijmegen, The Netherlands

Abstract:

Within the human organism, central and peripheral molecular clocks influence biochemistry, physiology and behavior to oscillate with a circadian (~ 24h) rhythmicity, thus controlling numerous physiological processes. Disrhythmic, i.e. out-of-sync body clocks lead to severe chronobiological impairments, such as cardiovascular disorders, neurological diseases, insomnia, and sleep disorder-related diseases, such as Alzheimer‘s Disease, arthritis, diabetes, or Parkinson‘s disease. In this context, Casein 1 Kinase d (CK1 δ) offers novel treatment opportunities for chronobiological diseases, since this kinase is involved in the regulation of a number of circadian clock-related proteins.

Here we report on the discovery and optimization of a class of novel, highly active CK1 δ inhibitors with improved selectivity profiles when compared to advanced competitor compounds, such as PF670462. Detailed enzymological studies on the frontrunner compound NBC 0459 show an ATP competitive, time dependent inhibition mode with an increased residence time on target. Most active compounds exhibit increased cellular efficacy, e.g. in a Tau phosphorylation assay. Initial PK studies on NBC 0459 show promising cerebrovascular permeability, qualifying the compound class as treatment modality for CNS-related conditions. Single administration of the lead compound within an in-vivo sleep-wake animal model promoted sleep and augmented NREM sleeping time significantly, thus demonstrating proof-of-concept for the therapeutic potential of CK1 δ inhibitors in diseases that are caused by dysregulated body clocks.