Casein Kinase 1 Delta/Epsilon Inhibitor Pf-5006739 Attenuates Opioid Drug-Seeking Behavior

Casein kinase 1 delta (CK1 delta) and casein kinase 1 epsilon (CK1 epsilon) 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 CK1 delta/epsilon inhibitors have now been identified that address this gap, through the design and synthesis of novel 4-[4-(4-fluoropheny1)-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 CK1 delta/epsilon (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 CK1 delta/epsilon inhibition in treating multiple indications in the clinic.