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 v 1.7/ Nav1.8 blockers for the treatment of pain

The voltage-gated sodium channel Na 1.7 is an attractive target for the treatment of pain based on the high level of target validation with genetic evidence linking Na 1.7 to pain in humans. Our effort to identify selective, CNS-penetrant Na 1.7 blockers with oral activity, improved selectivity, goo...

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Published in:Bioorganic & medicinal chemistry 2022-06, Vol.63, p.116743
Main Authors: Patel, Meena V, Peltier, Hillary M, Matulenko, Mark A, Koenig, John R, C Scanio, Marc J, Gum, Rebecca J, El-Kouhen, Odile F, Fricano, Meagan M, Lundgaard, Greta L, Neelands, Torben, Zhang, Xu-Feng, Zhan, Cenchen, Pai, Madhavi, Ghoreishi-Haack, Nayereh, Hudzik, Thomas, Gintant, Gary, Martin, Ruth, McGaraughty, Steve, Xu, Jun, Bow, Daniel, Kalvass, John C, Kym, Philip R, DeGoey, David A, Kort, Michael E
Format: Article
Language:English
Subjects:
Humans
Pain - drug therapy
Pain Management
Protein Isoforms
Sodium Channels - metabolism
Structure-Activity Relationship
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Summary:The voltage-gated sodium channel Na 1.7 is an attractive target for the treatment of pain based on the high level of target validation with genetic evidence linking Na 1.7 to pain in humans. Our effort to identify selective, CNS-penetrant Na 1.7 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 1.7 blockers. The design of these molecules focused on maintaining potency at Na 1.7, 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 1.8, another sodium channel isoform that is an active target for the development of new pain treatments.
ISSN:1464-3391