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)-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.
Subject(s)
Analgesics, Opioid/administration & dosage , Casein Kinase I/antagonists & inhibitors , Drug-Seeking Behavior/drug effects , Enzyme Inhibitors/pharmacology , Fentanyl/administration & dosage , Analysis of Variance , Animals , Circadian Rhythm/drug effects , Conditioning, Operant/drug effects , Cross-Over Studies , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemistry , Humans , Isoxazoles/pharmacology , Macaca fascicularis , Mice , Mice, Inbred C57BL , Protein Transport/drug effects , Pyrimidines/pharmacology , Rats , Rats, Sprague-Dawley , Reinforcement, Psychology , Self Administration , Time FactorsABSTRACT
The synthesis and structure-activity relationship (SAR) of a novel series of 3-(imidazolyl methyl)-3-aza-bicyclo[3.1.0]hexan-6-yl)methyl ethers, derived from a high throughput screening (HTS), are described. Subsequent optimization led to identification of potent, metabolically stable and orally available mGluR2 positive allosteric modulators (PAMs).
