Sulfonamides as Selective Na_V1.7 Inhibitors: Optimizing Potency and Pharmacokinetics to Enable in Vivo Target Engagement

Abstract

Human genetic evidence has identified the voltage-gated sodium channel Na_V1.7 as an attractive target for the treatment of pain. We initially identified naphthalene sulfonamide <b>3</b> as a potent and selective inhibitor of Na_V1.7. Optimization to reduce biliary clearance by balancing hydrophilicity and hydrophobicity (Log <i>D</i>) while maintaining Na_V1.7 potency led to the identification of quinazoline <b>16</b> (AM-2099). Compound <b>16</b> 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.