Casein Kinase 1未/蔚 Inhibitor PF-5006739 Attenuates Opioid Drug-Seeking Behavior

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• 作者：Travis T. Wager ; 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
• 刊名：ACS Chemical Neuroscience
• 出版年：2014
• 出版时间：December 17, 2014
• 年：2014
• 卷：5
• 期：12
• 页码：1253-1265
• 全文大小：601K
• ISSN：1948-7193

文摘

Casein kinase 1 delta (CK1未) and casein kinase 1 epsilon (CK1蔚) 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未/蔚 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 CK1未/蔚 (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未/蔚 inhibition in treating multiple indications in the clinic.

Keywords:

Casein kinase 1; CK1未; CK1蔚; PF-5006739; dual inhibitor; circadian rhythm; phase-delaying; opioid reinstatement; drug addiction