title: Ligand-protein interactions of selective casein kinase 1δ inhibitors.
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.
authors.affiliation: Pfizer Worldwide Research and Development , 700 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Scot
authors.initials: S
authors.lastname: Mente
authors.forename: Eric
authors.initials: E
authors.lastname: Arnold
authors.forename: Todd
authors.initials: T
authors.lastname: Butler
authors.forename: Subramanyam
authors.initials: S
authors.lastname: Chakrapani
authors.forename: Ramalakshmi
authors.initials: R
authors.lastname: Chandrasekaran
authors.forename: Kevin
authors.initials: K
authors.lastname: Cherry
authors.forename: Ken
authors.initials: K
authors.lastname: DiRico
authors.forename: Angela
authors.initials: A
authors.lastname: Doran
authors.forename: Katherine
authors.initials: K
authors.lastname: Fisher
authors.forename: Paul
authors.initials: P
authors.lastname: Galatsis
authors.forename: Michael
authors.initials: M
authors.lastname: Green
authors.forename: Matthew
authors.initials: M
authors.lastname: Hayward
authors.forename: John
authors.initials: J
authors.lastname: Humphrey
authors.forename: John
authors.initials: J
authors.lastname: Knafels
authors.forename: Jianke
authors.initials: J
authors.lastname: Li
authors.forename: Shenping
authors.initials: S
authors.lastname: Liu
authors.forename: Michael
authors.initials: M
authors.lastname: Marconi
authors.forename: Scott
authors.initials: S
authors.lastname: McDonald
authors.forename: Jeff
authors.initials: J
authors.lastname: Ohren
authors.forename: Vanessa
authors.initials: V
authors.lastname: Paradis
authors.forename: Blossom
authors.initials: B
authors.lastname: Sneed
authors.forename: Kevin
authors.initials: K
authors.lastname: Walton
authors.forename: Travis
authors.initials: T
authors.lastname: Wager
mesh_terms: D048148:Casein Kinase Idelta / Q000037:antagonists & inhibitors*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D011506:Proteins / Q000737:chemistry*
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; D011506:Proteins; D048148:Casein Kinase Idelta