Discovery of NaV1.7 Inhibitors for the Treatment of Pain

项目总结 我们计划的目标是开发一种安全有效的非阿片类止痛药，用于治疗 神经病理性疼痛，如与化疗引起的周围神经病变有关的疼痛，其目标是 电压门控钠离子通道的亚型，Nav1.7。电压门控钠通道参与 背根节神经元外周终末内伤害性信号的传递 背角内的突触终末。有十种哺乳动物亚型，Nav1.1-1.9和NAx。Nav1.7是 小直径有髓和无髓河豚毒素敏感钠通道最丰富 传入，在那里它已被证明调节兴奋性和设定动作电位的阈值。人类 由于一种罕见的遗传疾病，缺乏功能的Nav1.7无法体验几乎所有类型的疼痛。 开发Nav1.7系统抑制剂的努力因实现以下挑战而变得复杂 在隔膜、膈神经、心脏和中枢神经中表达的其他NAV亚型的选择性 对安全至关重要的系统。SiteOne治疗公司发现了一系列有效的、不依赖于国家的 比其他人类异构体具有1000倍选择性的Nav1.7抑制剂。在此项下进行的工作 该计划将支持一名主要候选人进入临床开发，作为治疗 神经性疼痛。

PROJECT SUMMARY The objective of our program is to develop a safe and effective nonopioid analgesic for the treatment of neuropathic pain, such as pain associated with chemotherapy-induced peripheral neuropathy, that targets an isoform of the voltage-gated sodium ion channel, NaV1.7. Voltage-gated sodium channels are involved in the transmission of nociceptive signals from their site of origin in the peripheral terminals of DRG neurons to the synaptic terminals in the dorsal horn. Ten mammalian isoforms exist, NaV1.1–1.9 and NaX. NaV1.7 is the most abundant tetrodotoxin-sensitive sodium channel in small diameter myelinated and unmyelinated afferents, where it has been shown to modulate excitability and set the threshold for action potentials. Humans lacking functional NaV1.7 due to a rare genetic condition are unable to experience almost all types of pain. Efforts to develop systemic inhibitors of NaV1.7 have been complicated by the challenge of achieving selectivity over other NaV isoforms expressed in the diaphragm, phrenic nerve, heart and central nervous system that are critical for safety. SiteOne Therapeutics has discovered a series of potent, state-independent NaV1.7 inhibitors that exhibit >1000-fold selectivity over other human isoforms. Work conducted under this program will support advancement of a lead candidate into clinical development as a therapeutic for neuropathic pain.