title: Development of New Benzenesulfonamides As Potent and Selective Nav1.7 Inhibitors for the Treatment of Pain.
abstract: By taking advantage of certain features in piperidine 4, we developed a novel series of cyclohexylamine- and piperidine-based benzenesulfonamides as potent and selective Nav1.7 inhibitors. However, compound 24, one of the early analogs, failed to reduce phase 2 flinching in the mouse formalin test even at a dose of 100 mpk PO due to insufficient dorsal root ganglion (DRG) exposure attributed to poor membrane permeability. Two analogs with improved membrane permeability showed much increased DRG concentrations at doses of 30 mpk PO, but, confoundingly, only one of these was effective in the formalin test. More data are needed to understand the disconnect between efficacy and exposure relationships.
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Yong-Jin
authors.identifier: 0000-0002-3452-6292
authors.initials: YJ
authors.lastname: Wu
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Jason
authors.initials: J
authors.lastname: Guernon
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Jianliang
authors.initials: J
authors.lastname: Shi
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Ditta
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Robbins
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Ramkumar
authors.initials: R
authors.lastname: Rajamani
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Amy
authors.initials: A
authors.lastname: Easton
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Amy
authors.initials: A
authors.lastname: Newton
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Clotilde
authors.initials: C
authors.lastname: Bourin
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Mosure
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Soars
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Knox
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Michele
authors.initials: M
authors.lastname: Matchett
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Rick L
authors.initials: RL
authors.lastname: Pieschl
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Debra J
authors.initials: DJ
authors.lastname: Post-Munson
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Shuya
authors.initials: S
authors.lastname: Wang
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: James
authors.initials: J
authors.lastname: Herrington
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: John
authors.initials: J
authors.lastname: Graef
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Newberry
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Bristow
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Meanwell
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Olson
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Lorin A
authors.initials: LA
authors.lastname: Thompson
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Dzierba
mesh_terms: D000700:Analgesics / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D055808:Drug Discovery; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000378:metabolism; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D013449:Sulfonamides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D061567:Voltage-Gated Sodium Channel Blockers / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000096926:Benzenesulfonamides
chemical_list: D000700:Analgesics; D062556:NAV1.7 Voltage-Gated Sodium Channel; D010880:Piperidines; D013449:Sulfonamides; D061567:Voltage-Gated Sodium Channel Blockers; D000096926:Benzenesulfonamides