PF 4800567 hydrochloride

Pharmacological studies of 3-[bis(3,3-diphenylpropyl)-amino]-propan-1-ol hydrochloride, (PF-244), a new cerebral vasodilator.[Pubmed:1174078]

Arzneimittelforschung. 1975 Apr;25(4):632-8.

Pharmacological effects of 3-[bis(3,3-diphenylpropyl)-amino]-propan-1-ol-hydrochloride (PF-244) mainly on cerebral and cardiovascular systems, were studied. PF-244 indicated a potent cerebral vasodilation effect and a marked increase in oxygen supply to cerebral tissue with only weak inotropic action and depressor effect. This cerebral vasodilation was more potent and specific than that of papaverine hydrochloride in regional cerebral flow. PF-244 also indicated an antibarium action, although it did not show the properties related to the cholinergic and/or adrenergic mechanism. PF-244 appears to be one of the potent cerebral vascular dilators, and the nature of its mechanism was discussed.

Casein kinase 1 delta (CK1delta) regulates period length of the mouse suprachiasmatic circadian clock in vitro.[Pubmed:20421981]

PLoS One. 2010 Apr 22;5(4):e10303.

BACKGROUND: Casein kinase 1 delta (CK1delta) plays a more prominent role in the regulation of circadian cycle length than its homologue casein kinase 1 epsilon (CK1epsilon) in peripheral tissues such as liver and embryonic fibroblasts. Mice lacking CK1delta die shortly after birth, so it has not been possible to assess the impact of loss of CK1delta on behavioral rhythms controlled by the master circadian oscillator in the suprachiasmatic nuclei (SCN). METHODOLOGY/PRINCIPAL FINDINGS: In the present study, mPER2::LUCIFERASE bioluminescence rhythms were monitored from SCN explants collected from neonatal mice. The data demonstrate that SCN explants from neonatal CK1delta-deficient mice oscillate, but with a longer circadian period than littermate controls. The cycle length of rhythms recorded from neonatal SCN explants of CK1epsilon-deficient mice did not differ from control explants. CONCLUSIONS/SIGNIFICANCE: The results indicate that CK1delta plays a more prominent role than CK1epsilon in the maintenance of 24-hour rhythms in the master circadian oscillator.

Entrainment of disrupted circadian behavior through inhibition of casein kinase 1 (CK1) enzymes.[Pubmed:20696890]

Proc Natl Acad Sci U S A. 2010 Aug 24;107(34):15240-5.

Circadian pacemaking requires the orderly synthesis, posttranslational modification, and degradation of clock proteins. In mammals, mutations in casein kinase 1 (CK1) epsilon or delta can alter the circadian period, but the particular functions of the WT isoforms within the pacemaker remain unclear. We selectively targeted WT CK1epsilon and CK1delta using pharmacological inhibitors (PF-4800567 and PF-670462, respectively) alongside genetic knockout and knockdown to reveal that CK1 activity is essential to molecular pacemaking. Moreover, CK1delta is the principal regulator of the clock period: pharmacological inhibition of CK1delta, but not CK1epsilon, significantly lengthened circadian rhythms in locomotor activity in vivo and molecular oscillations in the suprachiasmatic nucleus (SCN) and peripheral tissue slices in vitro. Period lengthening mediated by CK1delta inhibition was accompanied by nuclear retention of PER2 protein both in vitro and in vivo. Furthermore, phase mapping of the molecular clockwork in vitro showed that PF-670462 treatment lengthened the period in a phase-specific manner, selectively extending the duration of PER2-mediated transcriptional feedback. These findings suggested that CK1delta inhibition might be effective in increasing the amplitude and synchronization of disrupted circadian oscillators. This was tested using arrhythmic SCN slices derived from Vipr2(-/-) mice, in which PF-670462 treatment transiently restored robust circadian rhythms of PER2::Luc bioluminescence. Moreover, in mice rendered behaviorally arrhythmic by the Vipr2(-/-) mutation or by constant light, daily treatment with PF-670462 elicited robust 24-h activity cycles that persisted throughout treatment. Accordingly, selective pharmacological targeting of the endogenous circadian regulator CK1delta offers an avenue for therapeutic modulation of perturbed circadian behavior.

Selective inhibition of casein kinase 1 epsilon minimally alters circadian clock period.[Pubmed:19458106]

J Pharmacol Exp Ther. 2009 Aug;330(2):430-9.

The circadian clock links our daily cycles of sleep and activity to the external environment. Deregulation of the clock is implicated in a number of human disorders, including depression, seasonal affective disorder, and metabolic disorders. Casein kinase 1 epsilon (CK1epsilon) and casein kinase 1 delta (CK1delta) are closely related Ser-Thr protein kinases that serve as key clock regulators as demonstrated by mammalian mutations in each that dramatically alter the circadian period. Therefore, inhibitors of CK1delta/epsilon may have utility in treating circadian disorders. Although we previously demonstrated that a pan-CK1delta/epsilon inhibitor, 4-[3-cyclohexyl-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidin-2-ylamine (PF-670462), causes a significant phase delay in animal models of circadian rhythm, it remains unclear whether one of the kinases has a predominant role in regulating the circadian clock. To test this, we have characterized 3-(3-chloro-phenoxymethyl)-1-(tetrahydro-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin- 4-ylamine (PF-4800567), a novel and potent inhibitor of CK1epsilon (IC(50) = 32 nM) with greater than 20-fold selectivity over CK1delta. PF-4800567 completely blocks CK1epsilon-mediated PER3 nuclear localization and PER2 degradation. In cycling Rat1 fibroblasts and a mouse model of circadian rhythm, however, PF-4800567 has only a minimal effect on the circadian clock at concentrations substantially over its CK1epsilon IC(50). This is in contrast to the pan-CK1delta/epsilon inhibitor PF-670462 that robustly alters the circadian clock under similar conditions. These data indicate that CK1epsilon is not the predominant mediator of circadian timing relative to CK1delta. PF-4800567 should prove useful in probing unique roles between these two kinases in multiple signaling pathways.