Casein Kinase 1δ/ε Inhibitor PF-5006739 Attenuates Opioid Drug-Seeking Behavior

Abstract

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 (IC₅₀ = 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