title: 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)-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.
authors.affiliation: Pfizer Worldwide Research and Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Travis T
authors.initials: TT
authors.lastname: Wager
authors.forename: Ramalakshmi Y
authors.initials: RY
authors.lastname: Chandrasekaran
authors.forename: Jenifer
authors.initials: J
authors.lastname: Bradley
authors.forename: David
authors.initials: D
authors.lastname: Rubitski
authors.forename: Helen
authors.initials: H
authors.lastname: Berke
authors.forename: Scot
authors.initials: S
authors.lastname: Mente
authors.forename: Todd
authors.initials: T
authors.lastname: Butler
authors.forename: Angela
authors.initials: A
authors.lastname: Doran
authors.forename: Cheng
authors.initials: C
authors.lastname: Chang
authors.forename: Katherine
authors.initials: K
authors.lastname: Fisher
authors.forename: John
authors.initials: J
authors.lastname: Knafels
authors.forename: Shenping
authors.initials: S
authors.lastname: Liu
authors.forename: Jeff
authors.initials: J
authors.lastname: Ohren
authors.forename: Michael
authors.initials: M
authors.lastname: Marconi
authors.forename: George
authors.initials: G
authors.lastname: DeMarco
authors.forename: Blossom
authors.initials: B
authors.lastname: Sneed
authors.forename: Kevin
authors.initials: K
authors.lastname: Walton
authors.forename: David
authors.initials: D
authors.lastname: Horton
authors.forename: Amy
authors.initials: A
authors.lastname: Rosado
authors.forename: Andy
authors.initials: A
authors.lastname: Mead
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000704:Analysis of Variance; D000818:Animals; D047389:Casein Kinase I / Q000037:antagonists & inhibitors*; D002940:Circadian Rhythm / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005283:Fentanyl / Q000008:administration & dosage*; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D008252:Macaca fascicularis; D051379:Mice; D008810:Mice, Inbred C57BL; D021381:Protein Transport / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012054:Reinforcement, Psychology; D012646:Self Administration; D013997:Time Factors
chemical_list: C000600569:4-(4-(4-fluorophenyl)-1-(1-(1,2-oxazol-3-ylmethyl)piperidin-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine; D000701:Analgesics, Opioid; D004791:Enzyme Inhibitors; D007555:Isoxazoles; D011743:Pyrimidines; D047389:Casein Kinase I; D005283:Fentanyl
keywords: CK1δ; CK1ε; Casein kinase 1; PF-5006739; circadian rhythm; drug addiction; dual inhibitor; opioid reinstatement; phase-delaying