Substituted 5,6-(Dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-methanones as P2X7 Antagonists

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• 作者：Jeannie Ziff ; Dale A. Rudolph ; Brice Stenne ; Tatiana Koudriakova ; Brian Lord ; Pascal Bonaventure ; Timothy W. Lovenberg ; Nicholas I. Carruthers ; Anindya Bhattacharya ; Michael A. Letavic ; Brock T. Shireman
• 刊名：ACS Chemical Neuroscience
• 出版年：2016
• 出版时间：April 20, 2016
• 年：2016
• 卷：7
• 期：4
• 页码：498-504
• 全文大小：425K
• 年卷期：0
• ISSN：1948-7193

文摘

We describe the synthesis of a novel class of brain penetrating P2X7 antagonists with high potency at both the rat and human P2X7 receptors. Disclosed herein are druglike molecules with demonstrated target engagement of the rat P2X7 receptors after an oral dose. Specifically, compound 20 occupied the P2X7 receptors >80% over the 6 h time course as measured by an ex vivo radioligand binding experiment. In a dose–response assay, this molecule has a plasma EC₅₀ of 8 ng/mL. Overall, 20 has suitable druglike properties and pharmacokinetics in rat and dog. This molecule and others disclosed herein will serve as additional tools to elucidate the role of the P2X7 receptor in neuropsychiatric disorders.