2. Academic Validation
  3. Casein kinase 1δ/ε inhibitor PF-5006739 attenuates opioid drug-seeking behavior

Casein kinase 1δ/ε inhibitor PF-5006739 attenuates opioid drug-seeking behavior

  • ACS Chem Neurosci. 2014 Dec 17;5(12):1253-65. doi: 10.1021/cn500201x.
Travis T Wager 1,  Ramalakshmi Y Chandrasekaran,  Jenifer Bradley,  David Rubitski,  Helen Berke,  Scot Mente,  Todd Butler,  Angela Doran,  Cheng Chang,  Katherine Fisher,  John Knafels,  Shenping Liu,  Jeff Ohren,  Michael Marconi,  George DeMarco,  Blossom Sneed,  Kevin Walton,  David Horton,  Amy Rosado,  Andy Mead
Affiliations

Affiliation

  • 1 Pfizer Worldwide Research and Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
PMID: 25299732 DOI: 10.1021/cn500201x
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.

Keywords

CK1δ; CK1ε; Casein kinase 1; PF-5006739; circadian rhythm; drug addiction; dual inhibitor; opioid reinstatement; phase-delaying.

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