2. Academic Validation
  3. Ligand-protein interactions of selective casein kinase 1δ inhibitors

Ligand-protein interactions of selective casein kinase 1δ inhibitors

  • J Med Chem. 2013 Sep 12;56(17):6819-28. doi: 10.1021/jm4006324.
Scot Mente 1,  Eric Arnold,  Todd Butler,  Subramanyam Chakrapani,  Ramalakshmi Chandrasekaran,  Kevin Cherry,  Ken DiRico,  Angela Doran,  Katherine Fisher,  Paul Galatsis,  Michael Green,  Matthew Hayward,  John Humphrey,  John Knafels,  Jianke Li,  Shenping Liu,  Michael Marconi,  Scott McDonald,  Jeff Ohren,  Vanessa Paradis,  Blossom Sneed,  Kevin Walton,  Travis Wager
Affiliations

Affiliation

  • 1 Pfizer Worldwide Research and Development , 700 Main Street, Cambridge, Massachusetts 02139, United States.
PMID: 23919824 DOI: 10.1021/jm4006324
Abstract

Casein Kinase 1δ (CK1δ) and 1ε (CK1ε) are believed to be necessary Enzymes for the regulation of circadian rhythms in all mammals. On the basis of our previously published work demonstrating a CK1ε-preferring compound to be an ineffective circadian clock modulator, we have synthesized a series of pyrazole-substitued pyridine inhibitors, selective for the CK1δ isoform. Additionally, using structure-based drug design, we have been able to exploit differences in the hinge region between CK1δ and p38 to find selective inhibitors that have minimal p38 activity. The SAR, brain exposure, and the effect of these inhibitors on mouse circadian rhythms are described. The in vivo evaluation of these inhibitors demonstrates that selective inhibition of CK1δ at sufficient central exposure levels is capable of modulating circadian rhythms.

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