Benzoxazolinone aryl sulfonamides as potent, selective Na v 1.7 inhibitors with in vivo efficacy in a preclinical pain model

Studies on human genetics have suggested that inhibitors of the Na 1.7 voltage-gated sodium channel hold considerable promise as therapies for the treatment of chronic pain syndromes. Herein, we report novel, peripherally-restricted benzoxazolinone aryl sulfonamides as potent Na 1.7 inhibitors with...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2017-06, Vol.27 (12), p.2683-2688
Main Authors: Pero, Joseph E, Rossi, Michael A, Lehman, Hannah D G F, Kelly, 3rd, Michael J, Mulhearn, James J, Wolkenberg, Scott E, Cato, Matthew J, Clements, Michelle K, Daley, Christopher J, Filzen, Tracey, Finger, Eleftheria N, Gregan, Yun, Henze, Darrell A, Jovanovska, Aneta, Klein, Rebecca, Kraus, Richard L, Li, Yuxing, Liang, Annie, Majercak, John M, Panigel, Jacqueline, Urban, Mark O, Wang, Jixin, Wang, Ying-Hong, Houghton, Andrea K, Layton, Mark E
Format: Article
Language:English
Subjects:
Administration, Oral
Analgesics - administration & dosage
Analgesics - chemistry
Analgesics - pharmacology
Animals
Benzoxazoles - administration & dosage
Benzoxazoles - chemistry
Benzoxazoles - pharmacology
Biological Availability
Disease Models, Animal
Dose-Response Relationship, Drug
Formaldehyde - administration & dosage
Humans
Mice
Molecular Structure
Myocytes, Smooth Muscle - drug effects
Myocytes, Smooth Muscle - metabolism
NAV1.7 Voltage-Gated Sodium Channel - metabolism
Pain - chemically induced
Pain - drug therapy
Rats
Structure-Activity Relationship
Sulfonamides - administration & dosage
Sulfonamides - chemistry
Sulfonamides - pharmacology
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Summary:Studies on human genetics have suggested that inhibitors of the Na 1.7 voltage-gated sodium channel hold considerable promise as therapies for the treatment of chronic pain syndromes. Herein, we report novel, peripherally-restricted benzoxazolinone aryl sulfonamides as potent Na 1.7 inhibitors with excellent selectivity against the Na 1.5 isoform, which is expressed in the heart muscle. Elaboration of initial lead compound 3d afforded exemplar 13, which featured attractive physicochemical properties, outstanding lipophilic ligand efficiency and pharmacological selectivity against Na 1.5 exceeding 1000-fold. Key structure-activity relationships associated with oral bioavailability were leveraged to discover compound 17, which exhibited a comparable potency/selectivity profile as well as full efficacy following oral administration in a preclinical model indicative of antinociceptive behavior.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2017.04.040