Human genetic evidence has identified the voltage-gated sodium channel Na V 1.7 as an attractive target for the treatment of pain. We initially identified naphthalene sulfonamide 3 as a potent and selective inhibitor of Na V 1.7. Optimization to reduce biliary clearance by balancing hydrophilicity and hydrophobicity (Log D) while maintaining Na V 1.7 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. KEYWORDS: Sodium channel, Na V 1.7, Na V 1.5, pain, histamine scratching model H uman genetics has implicated the voltage-gated sodium channel Na V 1.7, which is expressed in nociceptive sensory neurons in dorsal root ganglia (DRG), 1 as a compelling target for pain.2−4 The primary challenge associated with the development of Na V 1.7 inhibitors has historically been achieving selectivity over the other eight Na V isoforms. These isoforms are differentially expressed throughout the body, but inhibition of Na V 1.5, which is expressed in cardiac tissue, is of particular concern as it has been shown to prolong the cardiac QRS wave in humans. 5,6 Previous efforts, including our own, have met with limited success. 4 Here we report the characterization, structure−activity relationship (SAR) and optimization of a series of sulfonamide-derived Na V 1.7 inhibitors. These efforts delivered an isoform-selective compound that was effective in a histamine-induced scratching model that is representative of Na V 1.7 target engagement. Recently Pfizer and Icagen described a series of heteroarylsulfonamide Na V 1.7 inhibitors with high levels of selectivity over Na V 1.5. 7−9 These results were reproduced by our group and are exemplified by compound 1 (Figure 1A). The lack of Na V 1.5 activity was noteworthy, and we envisioned this as a good starting point for our own lead optimization efforts, which would initially be aimed at addressing some of the liabilities and shortcomings associated with this class of compounds. Namely, this series suffered from low passive permeability and high clearance in rodents. We believed constraining the linker within a bicyclic core such as indole 2 or naphthalene 3 would afford a similar conformation and potentially help address the pharmacokinetic liabilities of this class of compounds. An overlay of global minima conformations of compounds 1, 2, and 3 supported this hypothesis ( Figure 1B), 10 and we were pleased to find that 2 and 3 were potent Na V 1.7 inhibitors and showed greater than 200-fold selectivity over Na V 1.5 ( Figure 1C). 11 In general, analogues in the naphthalene series demonstrated superior Na V 1.7 inhibition compared to the corresponding indole analogues, thus the naphthalene scaffold was chosen for further optimization. Additional profiling showed 3 also suffered from high clearance; however, we believed that 3 represented a promising starting poin...