1. 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.
- Author
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Patel MV, Peltier HM, Matulenko MA, Koenig JR, C Scanio MJ, Gum RJ, El-Kouhen OF, Fricano MM, Lundgaard GL, Neelands T, Zhang XF, Zhan C, Pai M, Ghoreishi-Haack N, Hudzik T, Gintant G, Martin R, McGaraughty S, Xu J, Bow D, Kalvass JC, Kym PR, DeGoey DA, and Kort ME
- Subjects
- Humans, Pain Management, Protein Isoforms, Structure-Activity Relationship, Pain drug therapy, Sodium Channels metabolism
- Abstract
The voltage-gated sodium channel Na
v 1.7 is an attractive target for the treatment of pain based on the high level of target validation with genetic evidence linking Nav 1.7 to pain in humans. Our effort to identify selective, CNS-penetrant Nav 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 Nav 1.7 blockers. The design of these molecules focused on maintaining potency at Nav 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 Nav 1.8, another sodium channel isoform that is an active target for the development of new pain treatments., (Copyright © 2022 Elsevier Ltd. All rights reserved.)- Published
- 2022
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