 |
PDBsum entry 4kb8
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Transferase/transferase inhibitor
|
PDB id
|
|
|
|
4kb8
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Ligand-Protein interactions of selective casein kinase 1δ inhibitors.
|
|
|
Authors
|
|
S.Mente,
E.Arnold,
T.Butler,
S.Chakrapani,
R.Chandrasekaran,
K.Cherry,
K.Dirico,
A.Doran,
K.Fisher,
P.Galatsis,
M.Green,
M.Hayward,
J.Humphrey,
J.Knafels,
J.Li,
S.Liu,
M.Marconi,
S.Mcdonald,
J.Ohren,
V.Paradis,
B.Sneed,
K.Walton,
T.Wager.
|
|
|
Ref.
|
|
J Med Chem, 2013,
56,
6819-6828.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
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.
|
|
|
|
|
|
|
