There remains an insufficient number of P2X7 receptor antagonists with adequate rodent potency, CNS permeability, and pharmacokinetic properties from which to evaluate CNS disease hypotheses preclinically. Herein, we describe the molecular pharmacology, safety, pharmacokinetics, and functional CNS target engagement of Lu AF27139, a novel rodent-active and CNS-penetrant P2X7 receptor antagonist. Lu AF27139 is highly selective and potent against rat, mouse, and human forms of the receptors. The rat pharmacokinetic profile is favorable with high oral bioavailability, modest clearance (0.79 L/(h kg)), and good CNS permeability. In vivo mouse CNS microdialysis studies of lipopolysaccharide (LPS)-primed and 2′(3′)-O-(benzoylbenzoyl)adenosine-5′-triphosphate (BzATP)-induced IL-1β release demonstrate functional CNS target engagement. Importantly, Lu AF27139 was without effect in standard in vitro and in vivo toxicity studies. Based on these properties, we believe Lu AF27139 will be a valuable tool for probing the role of the P2X7 receptor in rodent models of CNS diseases.

中文翻译：

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新型啮齿动物活性和CNS渗透性P2X7受体拮抗剂Lu AF27139的合成与表征

仍然缺乏足够数量的具有足够啮齿动物效力，中枢神经系统通透性和药代动力学性质的P2X7受体拮抗剂，可以从临床上评估中枢神经系统疾病假说。在这里，我们描述了Lu AF27139（一种新型的啮齿动物活性和CNS渗透性P2X7受体拮抗剂）的分子药理学，安全性，药代动力学和功能性CNS靶标结合。Lu AF27139具有高度选择性，对大鼠，小鼠和人类形式的受体具有强大的作用。大鼠的药代动力学特性良好，口服生物利用度高，清除率适中（0.79 L /（h kg）），并且具有良好的CNS渗透性。脂多糖（LPS）引发和2'（3'）- O的体内小鼠CNS微透析研究-（苯甲酰基苯甲酰基）腺苷-5'-三磷酸（BzATP）诱导的IL-1β释放证明功能性中枢神经系统靶标参与。重要的是，Lu AF27139在标准的体外和体内毒性研究中没有作用。基于这些特性，我们相信Lu AF27139将是探索P2X7受体在中枢神经系统疾病的啮齿动物模型中的重要工具。