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

Discovery of a Novel Class of State-Dependent NaV1.7 Inhibitors for the Treatment of Neuropathic Pain.
Chem Pharm Bull (Tokyo). 2020;68(7):653-663
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
Abstract
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).
PMID: 32612000 [PubMed - in process]

Source: Chemical and Pharmaceutical Bulletin - July 3, 2020 Category: Drugs & Pharmacology 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 Tags: Chem Pharm Bull (Tokyo) Source Type: research