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Discovery of a Novel Class of State-Dependent NaV1.7 Inhibitors for the Treatment of Neuropathic Pain.
Chemical & Pharmaceutical Bulletin ( IF 1.7 ) Pub Date : 2020-01-01 , DOI: 10.1248/cpb.c20-00126
Kyosuke Tanaka 1 , Hiroyuki Kobayashi 1 , Sayaka Suzuki 1 , Satoshi Shibuya 1 , Hiroko Kimoto 1 , Yuki Domon 1 , Kazufumi Kubota 1 , Yutaka Kitano 1 , Tomihisa Yokoyama 1 , Akiko Shimizugawa 1 , Ryuta Koishi 2 , Chie Fujiwara 1 , Daigo Asano 1 , Tsuyoshi Shinozuka 1
Affiliation  

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).

中文翻译:

发现一种新型的国家依赖性NaV1.7抑制剂,用于治疗神经性疼痛。

描述了新型的状态依赖性电压门控钠通道(NaV)1.7抑制剂的发现。通过在NaV1.7阻滞剂III中修饰酰胺或氨基甲酸酯键,进行了结构活性关系研究,从而鉴定了新型NaV1.7抑制剂2i(DS01171986)。化合物2i在浓度高达100μM的条件下对NaV1.7表现出状态依赖性抑制作用,而没有NaV1.1,NaV1.5或人类以太相关基因(hERG)。进一步的生物学分析成功地揭示了2i在神经性疼痛的小鼠模型(ED50:3.4 mg / kg)中具有有效的镇痛特性,并具有出色的中枢神经系统(CNS)安全裕度(> 600倍)。
更新日期:2020-01-01
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