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Papers of the Week


2020


Chem Pharm Bull (Tokyo)


68


7

Discovery of a Novel Class of State-Dependent Na1.7 Inhibitors for the Treatment of Neuropathic Pain.

Authors

Tanaka K, Kobayashi H, Suzuki S, Shibuya S, Kimoto H, Domon Y, Kubota K, Kitano Y, Yokoyama T, Shimizugawa A, Koishi R, Fujiwara C, Asano D, Shinozuka T
Chem Pharm Bull (Tokyo). 2020; 68(7):653-663.
PMID: 32612000.

Abstract

The discovery of a novel class of state-dependent voltage-gated sodium channel (Na)1.7 inhibitors is described. By the modification of amide or urethane bond in Na1.7 blocker III, structure-activity relationship studies that led to the identification of novel Na1.7 inhibitor 2i (DS01171986) were performed. Compound 2i exhibited state-dependent inhibition of Na1.7 without Na1.1, Na1.5 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: 3.4 mg/kg) with an excellent central nervous system (CNS) safety margin (> 600 fold).