Nav1.7 is a voltage gated sodium channel that has been implicated in nociception and pain signaling in humans. While several non-selective sodium channel pore blockers can demonstrate efficacy, their lack of selectivity is believed to be responsible for dose-dependent side effects that limit their clinical utility. Compounds selective for NaV1.7 have recently been reported that contain a sulfonamide pharmacophore. We recently reported the Xray crystal structure of a NaV1.7-selective arylsulfonamide complexed with voltage sensor domain 4 (VSD4). This structure shows that the anionic sulfonamide warhead forms an ion pair with Arg residues in S4 of VSD4 (Ahuga et al, 2015). We have used this structural information to design alternative anionic warheads in order to mitigate scaffold risk. Our presentation details the discovery and optimization of the first non-sulfonamide based selective Nav1.7 inhibitors that bind to VSD4 of hNaV1.7.<br/>GX-725 is a highly potent and selective Nav1.7 inhibitor that demonstrated analgesic activity in a transgenic mouse that expresses hNaV1.7 with an inherited erythromelalgia mutation is highlighted.

Discovery and optimization of a novel class of selective NaV1.7 antagonists

254th National Meeting (2017)

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