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 (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

Dopamine D3/D2 Receptor Antagonist PF-4363467 Attenuates Opioid Drug-Seeking Behavior without Concomitant D2 Side Effects

Dopamine receptor antagonism is a compelling molecular target for the treatment of a range of psychiatric disorders, including substance use disorders. From our corporate compound file, we identified a structurally unique D3 receptor (D3R) antagonist scaffold, <b>1</b>. Through a hybrid approach, we merged key pharmacophore elements from <b>1</b> and D3 agonist <b>2</b> to yield the novel D3R/D2R antagonist PF-4363467 (<b>3</b>). Compound <b>3</b> was designed to possess CNS drug-like properties as defined by its CNS MPO desirability score (≥4/6). In addition to good physicochemical properties, <b>3</b> exhibited low nanomolar affinity for the D3R (D3 <i>K</i>_i = 3.1 nM), good subtype selectivity over D2R (D2 <i>K</i>_i = 692 nM), and high selectivity for D3R versus other biogenic amine receptors. In vivo, <b>3</b> dose-dependently attenuated opioid self-administration and opioid drug-seeking behavior in a rat operant reinstatement model using animals trained to self-administer fentanyl. Further, traditional extrapyramidal symptoms (EPS), adverse side effects arising from D2R antagonism, were not observed despite high D2 receptor occupancy (RO) in rodents, suggesting that compound <b>3</b> has a unique in vivo profile. Collectively, our data support further investigation of dual D3R and D2R antagonists for the treatment of drug addiction