Journal of Medicinal Chemistry p. 2513 - 2525 (2017)
Update date:2022-09-26
Topics:
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
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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