Ligand-protein interactions of selective casein kinase 1δ inhibitors
| Autor: | John M. Humphrey, Shenping Liu, Jeff Ohren, Katherine Fisher, Ramalakshmi Yegna Chandrasekaran, Kevin M. Walton, Kevin Cherry, Butler Todd W, W. Scott McDonald, Eric P. Arnold, Jianke Li, Ken Dirico, Angela C. Doran, Blossom Sneed, Travis T. Wager, Subramanyam Chakrapani, Michael Eric Green, Scot Richard Mente, John D. Knafels, Matthew Merrill Hayward, Paul Galatsis, Vanessa Paradis, Michael Marconi |
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| Rok vydání: | 2013 |
| Předmět: |
Gene isoform
chemistry.chemical_classification Models Molecular Magnetic Resonance Spectroscopy p38 mitogen-activated protein kinases Circadian clock Proteins Ligands Mass Spectrometry Enzyme Biochemistry chemistry In vivo Casein Kinase Idelta Drug Discovery Molecular Medicine Casein kinase 1 Circadian rhythm Protein Kinase Inhibitors |
| Zdroj: | Journal of medicinal chemistry. 56(17) |
| ISSN: | 1520-4804 |
| Popis: | Casein kinase 1δ (CK1δ) and 1e (CK1e) 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 CK1e-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. |
| Databáze: | OpenAIRE |
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