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Development of New Benzenesulfonamides As Potent and Selective Nav1.7 Inhibitors for the Treatment of Pain.
Wu, Yong-Jin; Guernon, Jason; Shi, Jianliang; Ditta, Jonathan; Robbins, Kevin J; Rajamani, Ramkumar; Easton, Amy; Newton, Amy; Bourin, Clotilde; Mosure, Kathleen; Soars, Matthew G; Knox, Ronald J; Matchett, Michele; Pieschl, Rick L; Post-Munson, Debra J; Wang, Shuya; Herrington, James; Graef, John; Newberry, Kimberly; Bristow, Linda J; Meanwell, Nicholas A; Olson, Richard; Thompson, Lorin A; Dzierba, Carolyn.
Affiliation
  • Wu YJ; Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
  • Guernon J; Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
  • Shi J; Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
  • Ditta J; Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
  • Robbins KJ; Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
  • Rajamani R; Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
  • Easton A; Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
  • Newton A; Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
  • Bourin C; Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
  • Mosure K; Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
  • Soars MG; Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
  • Knox RJ; Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
  • Matchett M; Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
  • Pieschl RL; Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
  • Post-Munson DJ; Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
  • Wang S; Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
  • Herrington J; Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
  • Graef J; Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
  • Newberry K; Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
  • Bristow LJ; Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
  • Meanwell NA; Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
  • Olson R; Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
  • Thompson LA; Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
  • Dzierba C; Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
J Med Chem ; 60(6): 2513-2525, 2017 03 23.
Article in En | MEDLINE | ID: mdl-28234467
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pain / Sulfonamides / Voltage-Gated Sodium Channel Blockers / Analgesics Limits: Animals / Humans / Male Language: En Journal: J Med Chem Journal subject: QUIMICA Year: 2017 Document type: Article Affiliation country: Estados Unidos
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pain / Sulfonamides / Voltage-Gated Sodium Channel Blockers / Analgesics Limits: Animals / Humans / Male Language: En Journal: J Med Chem Journal subject: QUIMICA Year: 2017 Document type: Article Affiliation country: Estados Unidos