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ID: ALA3864175
Journal: ACS Med Chem Lett
Title: Sulfonamides as Selective NaV1.7 Inhibitors: Optimizing Potency and Pharmacokinetics to Enable in Vivo Target Engagement.
Authors: Marx IE, Dineen TA, Able J, Bode C, Bregman H, Chu-Moyer M, DiMauro EF, Du B, Foti RS, Fremeau RT, Gao H, Gunaydin H, Hall BE, Huang L, Kornecook T, Kreiman CR, La DS, Ligutti J, Lin MJ, Liu D, McDermott JS, Moyer BD, Peterson EA, Roberts JT, Rose P, Wang J, Youngblood BD, Yu V, Weiss MM.
Abstract: Human genetic evidence has identified the voltage-gated sodium channel NaV1.7 as an attractive target for the treatment of pain. We initially identified naphthalene sulfonamide 3 as a potent and selective inhibitor of NaV1.7. Optimization to reduce biliary clearance by balancing hydrophilicity and hydrophobicity (Log D) while maintaining NaV1.7 potency led to the identification of quinazoline 16 (AM-2099). Compound 16 demonstrated a favorable pharmacokinetic profile in rat and dog and demonstrated dose-dependent reduction of histamine-induced scratching bouts in a mouse behavioral model following oral dosing.
CiteXplore: 27994738