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 Nav1.7/ Nav1.8 blockers for the treatment of pain. (1st June 2022)

• Record Type: Journal Article
• 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.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 63(2022)
• Publication Date: 2022-06-01
• Subjects: Nav1.7 voltage-gated sodium channel type 7 -- CIP congenital insensitivity to pain -- SCN9A sodium channel, voltage-gated, type IX, R subunit -- VGSC voltage-gated sodium channel -- SAR structure activity relationship -- hERG human Ether-à-go-go-Related Gene -- FRET Fluorescence Resonance Energy Transfer -- MIA-OA mono-iodoacetate-induced osteoarthritis -- HEK human embryonic kidney -- CNS central nervous system -- PK pharmacokinetic -- Clint, u in- vitro intrinsic clearance, unbound -- F oral bioavailability -- TFA trifluoroacetic acid -- HATU (1-[Bis(dimethylamino)methylene]-1H-1, 2, 3-triazolo[4, 5–b]pyridinium 3-oxid hexafluorophosphate) -- TBTU O-(benzotriazol-1-yl)-N, N, N′, N′-tetramethyluronium tetrafluoroborate -- DMSO dimethyl sulfoxide -- DRG Dorsal root ganglion -- LMA Locomotor assay -- SNL Spinal nerve ligation; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2022.116743
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: The voltage-gated sodium channel Nav 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.