PF 5006739 - CAS 1293395-67-1
Category: Inhibitor
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PF 5006739 is a potent inhibitor of casein kinases 1 delta (CK1δ) and 1 epsilon (CK1ε) (IC50 values are 3.9 and 17 nM, respectively). It mediates circadian rhythm phase-delaying effects in vivo.
≥98% by HPLC
White solid
4-[4-(4-Fluorophenyl)-1-[1-(3-isoxazolylmethyl)-4-piperidinyl]-1H-imidazol-5-yl]-2-Pyrimidinamine; 4-{4-(4-Fluorophenyl)-1-[1-(1,2-oxazol-3-ylmethyl)piperidin-4-yl]-1H-imidazol-5-yl}pyrimidin-2-amine
Store in a cool and dry place (or refer to the Certificate of Analysis).
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1.Casein kinase 1δ/ε inhibitor PF-5006739 attenuates opioid drug-seeking behavior.
Wager TT;Chandrasekaran RY;Bradley J;Rubitski D;Berke H;Mente S;Butler T;Doran A;Chang C;Fisher K;Knafels J;Liu S;Ohren J;Marconi M;DeMarco G;Sneed B;Walton K;Horton D;Rosado A;Mead A ACS Chem Neurosci. 2014 Dec 17;5(12):1253-65. doi: 10.1021/cn500201x. Epub 2014 Oct 28.
Casein kinase 1 delta (CK1δ) and casein kinase 1 epsilon (CK1ε) inhibitors are potential therapeutic agents for a range of psychiatric disorders. The feasibility of developing a CNS kinase inhibitor has been limited by an inability to identify safe brain-penetrant compounds with high kinome selectivity. Guided by structure-based drug design, potent and selective CK1δ/ε inhibitors have now been identified that address this gap, through the design and synthesis of novel 4-[4-(4-fluorophenyl)-1-(piperidin-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine derivatives. PF-5006739 (6) possesses a desirable profile, with low nanomolar in vitro potency for CK1δ/ε (IC50 = 3.9 and 17.0 nM, respectively) and high kinome selectivity. In vivo, 6 demonstrated robust centrally mediated circadian rhythm phase-delaying effects in both nocturnal and diurnal animal models. Further, 6 dose-dependently attenuated opioid drug-seeking behavior in a rodent operant reinstatement model in animals trained to self-administer fentanyl. Collectively, our data supports further development of 6 as a promising candidate to test the hypothesis of CK1δ/ε inhibition in treating multiple indications in the clinic.
2.Targeting of the circadian clock via CK1δ/ε to improve glucose homeostasis in obesity.
Cunningham PS;Ahern SA;Smith LC;da Silva Santos CS;Wager TT;Bechtold DA Sci Rep. 2016 Jul 21;6:29983. doi: 10.1038/srep29983.
Growing evidence indicates that disruption of our internal timing system contributes to the incidence and severity of metabolic diseases, including obesity and type 2 diabetes. This is perhaps not surprising since components of the circadian clockwork are tightly coupled to metabolic processes across the body. In the current study, we assessed the impact of obesity on the circadian system in mice at a behavioural and molecular level, and determined whether pharmacological targeting of casein kinase 1δ and ε (CK1δ/ε), key regulators of the circadian clock, can confer metabolic benefit. We demonstrate that although behavioural rhythmicity was maintained in diet-induced obesity (DIO), gene expression profiling revealed tissue-specific alteration to the phase and amplitude of the molecular clockwork. Clock function was most significantly attenuated in visceral white adipose tissue (WAT) of DIO mice, and was coincident with elevated tissue inflammation, and dysregulation of clock-coupled metabolic regulators PPARα/γ. Further, we show that daily administration of a CK1δ/ε inhibitor (PF-5006739) improved glucose tolerance in both DIO and genetic (ob/ob) models of obesity. These data further implicate circadian clock disruption in obesity and associated metabolic disturbance, and suggest that targeting of the clock represents a therapeutic avenue for the treatment of metabolic disorders.
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CAS 1293395-67-1 PF 5006739

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