Discovery of (R)-(3-fluoropyrrolidin-1-yl)(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)quinolin-2-yl)methanone (ABBV-318) and analogs as small molecule Na_v1.7/ Nav1.8 blockers for the treatment of pain

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.