Details
| Stereochemistry | ACHIRAL |
| Molecular Formula | C19H20FN5 |
| Molecular Weight | 337.394 |
| Optical Activity | NONE |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 0 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
NC1=NC=CC(=N1)C2=C(N=CN2C3CCCCC3)C4=CC=C(F)C=C4
InChI
InChIKey=WUDBUIUHVNECTM-UHFFFAOYSA-N
InChI=1S/C19H20FN5/c20-14-8-6-13(7-9-14)17-18(16-10-11-22-19(21)24-16)25(12-23-17)15-4-2-1-3-5-15/h6-12,15H,1-5H2,(H2,21,22,24)
PF-670462 is a selective inhibitor of the δ- and ε-isoforms of casein kinase I, with IC50 values of 7.7 and 14 nM respectively, and >30 selectivity relative to 42 other kinases tested. Casein kinase Iε phosphorylates PER proteins, which are involved in setting the period of the circadian pacemaker or clock. PF-670462 is potent (IC50 7.7 nM) and effective in vivo (i.e. it induces profound phase delays in circadian periodicity). PF-670462 has being shown to have an ability to induce phase delays in circadian rhythms in rats, in which it is
rapidly metabolized, and in monkeys. A potential pharmacological
use of the compounds like PF-670462 could be for therapy of cognitive deficits in shift workers, mood changes in bipolar disorders, and phase advances in the sleep–wake cycle in elderly people. It has also being shown that Inhibition of the casein-kinase-1-ε/δ/ with PF-670462 prevents relapse-like alcohol drinking in rats, suggesting that CK1 inhibitors may be candidates for drug treatment development for alcoholism.
CNS Activity
Sources: https://www.ncbi.nlm.nih.gov/pubmed/19050854 | https://www.ncbi.nlm.nih.gov/pubmed/17502429
Curator's Comment: CNS penetrant and active in rodents
Originator
Approval Year
Targets
| Primary Target | Pharmacology | Condition | Potency |
|---|---|---|---|
Target ID: CHEMBL2828 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19458106 |
13.0 nM [IC50] | ||
| 7.7 nM [IC50] |
Conditions
| Condition | Modality | Targets | Highest Phase | Product |
|---|---|---|---|---|
| Primary | Unknown Approved UseUnknown |
|||
| Primary | Unknown Approved UseUnknown |
|||
| Primary | Unknown Approved UseUnknown |
PubMed
| Title | Date | PubMed |
|---|---|---|
| Acute inhibition of casein kinase 1δ/ε rapidly delays peripheral clock gene rhythms. | 2015-01 |
|
| Inhibition of the casein-kinase-1-ε/δ/ prevents relapse-like alcohol drinking. | 2012-08 |
|
| Protein kinases CK1 and CK2 as new targets for neurodegenerative diseases. | 2011-11 |
|
| Chronic treatment with a selective inhibitor of casein kinase I delta/epsilon yields cumulative phase delays in circadian rhythms. | 2010-07 |
|
| Inhibition of casein kinase I epsilon/delta produces phase shifts in the circadian rhythms of Cynomolgus monkeys. | 2009-07 |
Patents
Sample Use Guides
In Vivo Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/20407760
Curator's Comment: Can also be used i.p: Intraperitoneal PF-670462 (20-40 mg/kg) attenuated the locomotor stimulant response to MA (2 mg/kg) in mice
https://www.ncbi.nlm.nih.gov/pubmed/19050854
Rats: Gross motor activity was used to estimate the circadian rhythms of rats maintained under a 12 L:12 D cycle. PF-670462, 10 or 30 mg/kg/day s.c., was administered once daily for 20 days either at ZT6 or ZT11 (i.e., 6 or 11 h after light onset).
Route of Administration:
Other
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/20696890
Curator's Comment: Primary lung fibroblast cells obtained from WT, Ck1ε
tau mutant, and Ck1ε −/− mice bred on a PER2::Luc
reporter background were used.
Treatment with
PF-670462 caused significant dose-dependent lengthening of the
circadian period: high-dose PF-670462 (1 uM) extended the period
in WT fibroblasts to 33 h
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