2. Academic Validation
  3. 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

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

  • Bioorg Med Chem. 2022 Jun 1;63:116743. doi: 10.1016/j.bmc.2022.116743.
Meena V Patel 1,  Hillary M Peltier 2,  Mark A Matulenko 2,  John R Koenig 2,  Marc J C Scanio 2,  Rebecca J Gum 2,  Odile F El-Kouhen 2,  Meagan M Fricano 2,  Greta L Lundgaard 2,  Torben Neelands 2,  Xu-Feng Zhang 2,  Cenchen Zhan 2,  Madhavi Pai 2,  Nayereh Ghoreishi-Haack 2,  Thomas Hudzik 2,  Gary Gintant 2,  Ruth Martin 2,  Steve McGaraughty 2,  Jun Xu 2,  Daniel Bow 2,  John C Kalvass 2,  Philip R Kym 2,  David A DeGoey 2,  Michael E Kort 2
Affiliations

Affiliations

  • 1 AbbVie, Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, USA. Electronic address: [email protected].
  • 2 AbbVie, Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, USA.
PMID: 35436748 DOI: 10.1016/j.bmc.2022.116743
Abstract

The voltage-gated Sodium Channel Nav1.7 is an attractive target for the treatment of pain based on the high level of target validation with genetic evidence linking Nav1.7 to pain in humans. Our effort to identify selective, CNS-penetrant Nav1.7 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 Nav1.7 blockers. The design of these molecules focused on maintaining potency at Nav1.7, 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 Nav1.8, another Sodium Channel isoform that is an active target for the development of new pain treatments.

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