1 research outputs found
Casein Kinase 1δ/ε Inhibitor PF-5006739 Attenuates Opioid Drug-Seeking Behavior
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)-1<i>H</i>-imidazol-5-yl]pyrimidin-2-amine derivatives. PF-5006739
(<b>6</b>) possesses a desirable profile, with low nanomolar
in vitro potency for CK1δ/ε (IC<sub>50</sub> = 3.9 and
17.0 nM, respectively) and high kinome selectivity. In vivo, <b>6</b> demonstrated robust centrally mediated circadian rhythm
phase-delaying effects in both nocturnal and diurnal animal models.
Further, <b>6</b> 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 <b>6</b> as a promising candidate to test the
hypothesis of CK1δ/ε inhibition in treating multiple indications
in the clinic