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The discovery of a novel class of state-dependent voltage-gated sodium channel (Na V )1.7 inhibitors is described. By the modification of amide or urethane bond in Na V 1.7 blocker III, structure-activity relationship studies that led to the identification of novel Na V 1.7 inhibitor 2i (DS01171986) were performed. Compound 2i exhibited state-dependent inhibition of Na V 1.7 without Na V 1.1, Na V 1.5 or human ether-a-go-go related gene (hERG) liabilities at concentrations up to 100 μM. Further biological profiling successfully revealed that 2i possessed potent analgesic properties in a murine model of neuropathic pain (ED 50 : 3.4 mg/kg) with an excellent central nervous system (CNS) safety margin (&gt; 600 fold).

Discovery of a Novel Class of State-Dependent Na<sub>V</sub>1.7 Inhibitors for the Treatment of Neuropathic Pain