Discovery of non-zwitterionic aryl sulfonamides as Nav1.7 inhibitors with efficacy in preclinical behavioral models and translational measures of nociceptive neuron activation

• Published in: Bioorganic & medicinal chemistry Vol. 25; no. 20; pp. 5490 - 5505
• Main Authors: Wu, Yong-Jin, Guernon, Jason, McClure, Andrea, Luo, Guanglin, Rajamani, Ramkumar, Ng, Alicia, Easton, Amy, Newton, Amy, Bourin, Clotilde, Parker, Dawn, Mosure, Kathleen, Barnaby, Omar, Soars, Matthew G., Knox, Ronald J., Matchett, Michele, Pieschl, Rick, Herrington, James, Chen, Ping, Sivarao, D.V., Bristow, Linda J., Meanwell, Nicholas A., Bronson, Joanne, Olson, Richard, Thompson, Lorin A., Dzierba, Carolyn
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 15.10.2017
• Subjects: Benzenesulfonamide; Membrane permeability; Nav1.7 inhibitor; Neuropathic and inflammatory pain; Nociceptive flexion reflex (NFR); Translational electromyogram; Translational electromyogram; Neuropathic and inflammatory pain; Nociceptive flexion reflex (NFR); Benzenesulfonamide; Membrane permeability; Nav1.7 inhibitor
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2017.08.012

[Display omitted] Since zwitterionic benzenesulfonamide Nav1.7 inhibitors suffer from poor membrane permeability, we sought to eliminate this characteristic by replacing the basic moiety with non-basic bicyclic acetals and monocyclic ethers. These efforts led to the discovery of the non-zwitterionic aryl sulfonamide 49 as a selective Nav1.7 inhibitor with improved membrane permeability. Despite its moderate cellular activity, 49 exhibited robust efficacy in mouse models of neuropathic and inflammatory pain and modulated translational electromyogram measures associated with activation of nociceptive neurons.