Global Pharmaceutical Research and Development, Abbott Laboratories, Dept R4PM, Bldg. AP9A, 100 Abbott Park Road, Abbott Park, IL 60064-6117, United States.
Bioorg Med Chem. 2010 Nov 15;18(22):7816-25. doi: 10.1016/j.bmc.2010.09.057. Epub 2010 Sep 29.
Na(v)1.8 (also known as PN3) is a tetrodotoxin-resistant (TTx-r) voltage-gated sodium channel (VGSC) that is highly expressed on small diameter sensory neurons. It has been implicated in the pathophysiology of inflammatory and neuropathic pain, and we envisioned that selective blockade of Na(v)1.8 would be analgesic, while reducing adverse events typically associated with non-selective VGSC blocking therapeutic agents. Herein, we describe the preparation and characterization of a series of 6-aryl-2-pyrazinecarboxamides, which are potent blockers of the human Na(v)1.8 channel and also block TTx-r sodium currents in rat dorsal root ganglia (DRG) neurons. Selected derivatives display selectivity versus human Na(v)1.2. We further demonstrate that an example from this series is orally bioavailable and produces antinociceptive activity in vivo in a rodent model of neuropathic pain following oral administration.
Nav1.8（也称为 PN3）是一种河豚毒素抗性（TTx-r）电压门控钠离子通道（VGSC），在小直径感觉神经元上高度表达。它与炎症性和神经性疼痛的病理生理学有关，我们设想选择性阻断 Nav1.8 将具有镇痛作用，同时减少与非选择性 VGSC 阻断治疗剂相关的不良反应。在此，我们描述了一系列 6-芳基-2-吡嗪甲酰胺的制备和表征，这些化合物是有效的人 Nav1.8 通道阻断剂，也可阻断大鼠背根神经节（DRG）神经元中的 TTx-r 钠电流。选定的衍生物对人 Nav1.2 具有选择性。我们进一步证明，该系列中的一个实例具有口服生物利用度，并在神经性疼痛的啮齿动物模型中经口服给药后产生体内抗伤害感受活性。
