The voltage-gated sodium channel Na_v1.7 is an attractive target for the treatment of pain based on the high level of target validation with genetic evidence linking Na_v1.7 to pain in humans. Our effort to identify selective, CNS-penetrant Na_v1.7 blockers with oral activity, improved selectivity, good drug-like properties, and safety led to the discovery of 2-substituted quinolines and quinolones as potent small molecule Na_v1.7 blockers. The design of these molecules focused on maintaining potency at Na_v1.7, improving selectivity over the hERG channel, and overcoming phospholipidosis observed with the initial leads. The structure-activity relationship (SAR) studies leading to the discovery of (R)-(3-fluoropyrrolidin-1-yl)(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)quinolin-2-yl)methanone (ABBV-318) are described herein. ABBV-318 displayed robust in vivo efficacy in both inflammatory and neuropathic rodent models of pain. ABBV-318 also inhibited Na_v1.8, another sodium channel isoform that is an active target for the development of new pain treatments.

电压门控钠通道 Na _v 1.7 是治疗疼痛的一个有吸引力的目标，基于高水平的目标验证以及将 Na _v 1.7 与人类疼痛联系起来的遗传证据。我们努力识别具有口服活性、选择性提高、良好的药物样特性和安全性的选择性、CNS 渗透性 Na _v 1.7 阻滞剂，导致发现 2-取代的喹啉和喹诺酮类药物是有效的小分子 Na _v 1.7 阻滞剂。这些分子的设计侧重于保持 Na _v 1.7 的效力，提高对 hERG 通道的选择性，并克服在初始引线中观察到的磷脂沉积。结构-活性关系 (SAR) 研究导致发现 ( R)-(3-氟吡咯烷-1-基)(6-((5-(三氟甲基)吡啶-2-基)氧基)喹啉-2-基)甲酮(ABBV-318)在本文中进行了描述。ABBV-318在炎症性和神经性啮齿动物疼痛模型中显示出强大的体内功效。ABBV-318 还抑制 Na _v 1.8，这是另一种钠通道异构体，是开发新的疼痛治疗的积极目标。