1443373-17-8Relevant articles and documents
Sulfonamides as Selective NaV1.7 Inhibitors: Optimizing Potency and Pharmacokinetics to Enable in Vivo Target Engagement
Marx, Isaac E.,Dineen, Thomas A.,Able, Jessica,Bode, Christiane,Bregman, Howard,Chu-Moyer, Margaret,Dimauro, Erin F.,Du, Bingfan,Foti, Robert S.,Fremeau, Robert T.,Gao, Hua,Gunaydin, Hakan,Hall, Brian E.,Huang, Liyue,Kornecook, Thomas,Kreiman, Charles R.,La, Daniel S.,Ligutti, Joseph,Lin, Min-Hwa Jasmine,Liu, Dong,McDermott, Jeff S.,Moyer, Bryan D.,Peterson, Emily A.,Roberts, Jonathan T.,Rose, Paul,Wang, Jean,Youngblood, Beth D.,Yu, Violeta,Weiss, Matthew M.
, p. 1062 - 1067 (2016)
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.
