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

[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...