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.

Autor: Patel MV; AbbVie, Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, USA. Electronic address: meena.v.patel@abbvie.com., Peltier HM; AbbVie, Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, USA., Matulenko MA; AbbVie, Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, USA., Koenig JR; AbbVie, Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, USA., C Scanio MJ; AbbVie, Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, USA., Gum RJ; AbbVie, Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, USA., El-Kouhen OF; AbbVie, Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, USA., Fricano MM; AbbVie, Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, USA., Lundgaard GL; AbbVie, Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, USA., Neelands T; AbbVie, Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, USA., Zhang XF; AbbVie, Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, USA., Zhan C; AbbVie, Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, USA., Pai M; AbbVie, Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, USA., Ghoreishi-Haack N; AbbVie, Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, USA., Hudzik T; AbbVie, Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, USA., Gintant G; AbbVie, Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, USA., Martin R; AbbVie, Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, USA., McGaraughty S; AbbVie, Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, USA., Xu J; AbbVie, Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, USA., Bow D; AbbVie, Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, USA., Kalvass JC; AbbVie, Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, USA., Kym PR; AbbVie, Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, USA., DeGoey DA; AbbVie, Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, USA., Kort ME; AbbVie, Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, USA.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2022 Jun 01; Vol. 63, pp. 116743. Date of Electronic Publication: 2022 Apr 11.
DOI: 10.1016/j.bmc.2022.116743
Abstrakt: 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 Na v 1.7 to pain in humans. Our effort to identify selective, CNS-penetrant Na v 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 v 1.7 blockers. The design of these molecules focused on maintaining potency at Na v 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 v 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.)
Databáze: MEDLINE
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