Discovery of non-zwitterionic aryl sulfonamides as Na v 1.7 inhibitors with efficacy in preclinical behavioral models and translational measures of nociceptive neuron activation

Since zwitterionic benzenesulfonamide Na 1.7 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...

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Published inBioorganic & medicinal chemistry Vol. 25; no. 20; p. 5490
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
LanguageEnglish
Published England 15.10.2017
Subjects
Administration, Oral
Animals
Chronic Pain - chemically induced
Chronic Pain - drug therapy
Disease Models, Animal
Dose-Response Relationship, Drug
Drug Discovery
Freund's Adjuvant
HEK293 Cells
Humans
Inflammation - chemically induced
Inflammation - drug therapy
Male
Mice
Models, Biological
Molecular Structure
NAV1.7 Voltage-Gated Sodium Channel - metabolism
Neurons - drug effects
Neurons - metabolism
Nociception - drug effects
Structure-Activity Relationship
Sulfonamides - administration & dosage
Sulfonamides - chemistry
Sulfonamides - pharmacology
Membrane permeability
Translational electromyogram
Na(v)1.7 inhibitor
Neuropathic and inflammatory pain
Nociceptive flexion reflex (NFR)
Benzenesulfonamide
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Summary:Since zwitterionic benzenesulfonamide Na 1.7 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 Na 1.7 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.
ISSN:1464-3391