Ligand鈥揚rotein Interactions of Selective Casein Kinase 1未 Inhibitors

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• 作者：Scot Mente ; 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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：September 12, 2013
• 年：2013
• 卷：56
• 期：17
• 页码：6819-6828
• 全文大小：439K
• 年卷期：v.56,no.17(September 12, 2013)
• ISSN：1520-4804

文摘

Casein kinase 1未 (CK1未) and 1蔚 (CK1蔚) 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 CK1蔚-preferring compound to be an ineffective circadian clock modulator, we have synthesized a series of pyrazole-substitued pyridine inhibitors, selective for the CK1未 isoform. Additionally, using structure-based drug design, we have been able to exploit differences in the hinge region between CK1未 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 CK1未 at sufficient central exposure levels is capable of modulating circadian rhythms.