摘要：The discovery of a novel class of state-dependent voltage-gated sodium channel (NaV )1.7 inhibitors is described. By the modification of amide or urethane bond in NaV 1.7 blocker III , structure–activity relationship studies that led to the identification of novel NaV 1.7 inhibitor 2i (DS01171986) were performed. Compound 2i exhibited state-dependent inhibition of NaV 1.7 without NaV 1.1, NaV 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 (ED50 : 3.4 mg/kg) with an excellent central nervous system (CNS) safety margin (> 600 fold).
关键词：voltage-gated sodium channel;pain;central nervous system (CNS) side effect;quinolone;urethane
