Discovery of a Novel Class of State-Dependent NaV1.7 Inhibitors for the Treatment of Neuropathic Pain.

Chemical & pharmaceutical bulletin 2020

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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 NaV1.7 blocker III, structure-activity relationship studies that led to the identification of novel NaV1.7 inhibitor 2i (DS01171986) were performed. Compound 2i exhibited state-dependent inhibition of NaV1.7 without NaV1.1, NaV1.5 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).

Citation

Kyosuke Tanaka, Hiroyuki Kobayashi, Sayaka Suzuki, Satoshi Shibuya, Hiroko Kimoto, Yuki Domon, Kazufumi Kubota, Yutaka Kitano, Tomihisa Yokoyama, Akiko Shimizugawa, Ryuta Koishi, Chie Fujiwara, Daigo Asano, Tsuyoshi Shinozuka. Discovery of a Novel Class of State-Dependent NaV1.7 Inhibitors for the Treatment of Neuropathic Pain. Chemical & pharmaceutical bulletin. 2020;68(7):653-663