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

• Published in: Bioorganic & medicinal chemistry letters Vol. 27; no. 12; pp. 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: Journal Article
• Language: English
• Published: England 15.06.2017
• 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; Pharmacological selectivity; Oral bioavailability; Na(v)1.7 inhibition; Chronic pain; Voltage-gated sodium channel
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2017.04.040

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.