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Discovery of Vixotrigine: A Novel Use-Dependent Sodium Channel Blocker for the Treatment of Trigeminal Neuralgia.
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-07-16 , DOI: 10.1021/acsmedchemlett.0c00263 David R Witty 1 , Giuseppe Alvaro 1 , Dominique Derjean 1 , Gerard M P Giblin 1 , Kevin Gunn 1 , Charles Large 1 , David T Macpherson 1 , Valerie Morisset 1 , Davina Owen 1 , Joanne Palmer 1 , Francois Rugiero 1 , Simon Tate 1 , Christopher A Hinckley 2 , Himanshu Naik 2
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-07-16 , DOI: 10.1021/acsmedchemlett.0c00263 David R Witty 1 , Giuseppe Alvaro 1 , Dominique Derjean 1 , Gerard M P Giblin 1 , Kevin Gunn 1 , Charles Large 1 , David T Macpherson 1 , Valerie Morisset 1 , Davina Owen 1 , Joanne Palmer 1 , Francois Rugiero 1 , Simon Tate 1 , Christopher A Hinckley 2 , Himanshu Naik 2
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Drugs that block voltage-gated sodium channels (NaVs) have utility in treating conditions including pain, epilepsy, and cardiac arrhythmias and as anesthetics ( Lancet Neurol.20109413424; Expert Opin. Ther. Pat.201020755779). The identification of compounds with improved efficacy and safety is a key aim for the discovery of improved NaV blocking drugs ( Comprehensive Medicinal Chemistry III; Elsevier, 2017; pp 131−175). We report the identification of a novel class of brain penetrant and voltage-gated sodium channel blockers, leading to the discovery of vixotrigine, a use-dependent sodium channel blocker with activity in in vivo models of pain. Vixotrigine has excellent physiocochemical properties for drug development, and both preclinical and clinical data support a safety profile suitable for potential use in neuropathic pain and other conditions. It has shown efficacy in a Phase II study for pain associated with trigeminal neuralgia.
中文翻译：
维索三嗪的发现：一种用于治疗三叉神经痛的新型依赖性钠通道阻滞剂。
阻断电压门控钠通道 (Na V s) 的药物可用于治疗疼痛、癫痫和心律失常等疾病，也可用作麻醉剂 ( Lancet Neurol. 2010 9 413424； Expert Opin. Ther. Pat. 2010 20 755779)。鉴定具有更高功效和安全性的化合物是发现改进的 Na V阻断药物的关键目标（综合药物化学 III ；Elsevier， 2017 ；第 131−175 页）。我们报告了一类新型脑渗透性和电压门控钠通道阻滞剂的鉴定，从而发现了维索三嗪，一种在体内疼痛模型中具有活性的使用依赖性钠通道阻滞剂。 Vixotrigine 具有适合药物开发的优异理化特性，临床前和临床数据都支持其安全性，适合潜在用于神经性疼痛和其他疾病。 II 期研究显示它对三叉神经痛相关疼痛有效。
更新日期：2020-09-10
中文翻译：
维索三嗪的发现：一种用于治疗三叉神经痛的新型依赖性钠通道阻滞剂。
阻断电压门控钠通道 (Na V s) 的药物可用于治疗疼痛、癫痫和心律失常等疾病，也可用作麻醉剂 ( Lancet Neurol. 2010 9 413424； Expert Opin. Ther. Pat. 2010 20 755779)。鉴定具有更高功效和安全性的化合物是发现改进的 Na V阻断药物的关键目标（综合药物化学 III ；Elsevier， 2017 ；第 131−175 页）。我们报告了一类新型脑渗透性和电压门控钠通道阻滞剂的鉴定，从而发现了维索三嗪，一种在体内疼痛模型中具有活性的使用依赖性钠通道阻滞剂。 Vixotrigine 具有适合药物开发的优异理化特性，临床前和临床数据都支持其安全性，适合潜在用于神经性疼痛和其他疾病。 II 期研究显示它对三叉神经痛相关疼痛有效。
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