A randomised, double-blind, placebo-controlled, four-way crossover, two-part study investigating the pharmacodynamic effect of DSP-2230 using the ID Capsaicin and UVB models in healthy male subjects, using pregabalin and ibuprofen lysine as positive controls.

开始日期2013-01-07

申办/合作机构

Sunovion Pharmaceuticals Europe Ltd.

100 项与 DSP-2230 相关的临床结果

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100 项与 DSP-2230 相关的转化医学

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100 项与 DSP-2230 相关的专利（医药）

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项与 DSP-2230 相关的文献（医药）

2024-08-01·Biochemical and Biophysical Research Communications

Unique electrophysiological property of a novel Nav1.7, Nav1.8, and Nav1.9 sodium channel blocker, ANP-230

Article

作者: Kudo, Takehiro ; Takada, Yoshinori ; Ishibashi, Fumiaki ; Oyamada, Yoshihiro ; Maezawa, Yasuyo ; Ikeda, Kazuhito ; Honda, Shigeyuki ; Kamei, Tatsuya ; Yamane, Hana

Voltage-gated sodium channel subtypes, Nav1.7, Nav1.8, and Nav1.9 are predominantly expressed in peripheral sensory neurons. Recent genetic studies have revealed that they are involved in pathological pain processing and that the blockade of Nav1.7, Nav1.8, or Nav1.9 will become a promising pharmacotherapy especially for neuropathic pain. A growing number of drug discovery programs have targeted either of the subtypes to obtain a selective inhibitor which can provide pain relief without affecting the cardiovascular and central nervous systems, though none of them has been approved yet. Here we describe the in vitro characteristics of ANP-230, a novel sodium channel blocker under clinical development. Surprisingly, ANP-230 was shown to block three pain-related subtypes, human Nav1.7, Nav1.8, and Nav1.9 with similar potency, but had only low inhibitory activity to human cardiac Nav1.5 channel and rat central Nav channels. The voltage clamp experiments using different step pulse protocols revealed that ANP-230 had a "tonic block" mode of action without state- and use-dependency. In addition, ANP-230 caused a depolarizing shift of the activation curve and decelerated gating kinetics in human Nav1.7-stably expressing cells. The depolarizing shift of activation curve was commonly observed in human Nav1.8-stably expressing cells as well as rat dorsal root ganglion neurons. These data suggested a quite unique mechanism of Nav channel inhibition by ANP-230. Finally, ANP-230 reduced excitability of rat dorsal root ganglion neurons in a concentration dependent manner. Collectively, these promising results indicate that ANP-230 could be a potent drug for neuropathic pain.

2023-04-01·Heliyon

Reduced pain sensitivity of episodic pain syndrome model mice carrying a Nav1.9 mutation by ANP-230, a novel sodium channel blocker

Article

作者: Okuda, Hiroko ; Oyamada, Yoshihiro ; Inoue, Sumiko ; Youssefian, Shohab ; Koizumi, Akio

The sodium channel Nav1.9 is expressed in the sensory neurons of small diameter dorsal root ganglia that transmit pain signals, and gain-of-function Nav1.9 mutations have been associated with both painful and painless disorders. We initially determined that some Nav1.9 mutations are responsible for familial episodic pain syndrome observed in the Japanese population. We therefore generated model mice harboring one of the more painful Japanese mutations, R222S, and determined that dorsal root ganglia hyperexcitability was the cause of the associated pain. ANP-230 is a novel non-opioid drug with strong inhibitory effects on Nav1.7, 1.8 and 1.9, and is currently under clinical trials for patients suffering from familial episodic pain syndrome. However, little is known about its mechanism of action and effects on pain sensitivity. In this study, we therefore investigated the inhibitory effects of ANP-230 on the hypersensitivity of Nav1.9 p.R222S mutant model mouse to pain. In behavioral tests, ANP-230 reduced the pain response of the mice, particularly to heat or mechanical stimuli, in a concentration- and time-dependent manner. Furthermore, ANP-230 suppressed the repetitive firing of dorsal root ganglion neurons of these mutant mice. Our results clearly demonstrate that ANP-230 is an effective analgesic for familial episodic pain syndrome resulting from DRG neuron hyperexcitability, and that such analgesic effects are likely to be of clinical significance.

项与 DSP-2230 相关的新闻（医药）

2023-12-03

·今日头条

成为院士后，颜宁首次发文！

本文为转化医学网原创，转载请注明出处作者：Jerry 导读： 11月22日，2023年两院院士增选结果正式揭晓。据中国科学院当日发布的名单，45岁的颜宁新当选中国科学院院士。成为院士后，颜宁与团队成员合作发表了首篇文章。近日，清华大学/深圳医学科学院颜宁团队在Channels 发表了题为“A structural atlas of druggable sites on Nav channels”的综述文章，该综述将概述Nav通道结构药理学的最新进展，包括配体结合Nav通道的结构图谱。这些发现为未来的药物开发奠定了重要的基础。 https://doi.org/10.1080/19336950.2023.2287832 研究背景 01 电压门控钠(Nav)通道是一种跨膜蛋白，在膜去极化时选择性地输入钠离子。在神经细胞和肌肉细胞等可兴奋细胞中，Nav通道对电信号传递至关重要，并负责动作电位的产生和传播。大约70年前，霍奇金和赫胥黎首次记录了钠电流的电压依赖性激活，标志着动作电位的发现。Hille研究了Nav通道的离子选择性，并提出了“四势垒，三位点模型”来描述钠离子的选择性。他还分析了局麻药与相关Nav靶向药物的结合方式。Armstrong和Bezanilla使用高分辨率电生理记录方法测量门控电流，并探索了Nav通道快速失活的过程和决定因素。在20世纪80年代早期，Barchi和Catterall小组研究了Nav通道的生化特性;Numa等报道了Nav通道成孔亚基(α亚基)的编码序列。总之，这些里程碑建立了Nav通道的功能、工作机制和结构特性的早期概念。 Nav通道属于电压门控离子通道(VGIC)超族。它们通常由核心α亚基和辅助β亚基(β1-β4)组成，核心α亚基单独具有足够的通道活性，辅助β亚基有助于膜定位和通道调节。α亚基是一个长度约为2000个残基的单一多肽，折叠成4个同源重复(重复I-IV)。每个重复序列由6个跨膜螺旋组成(S1-S6)，其中4个重复序列中的S5和S6构成离子渗透孔域(PD)，每个重复序列中的S1-S4构成侧翼电压感应域(VSD)。S5和S6之间的序列组装成细胞外环(ecl)和离子选择性过滤器(SF)。四个不同的残基，Asp/Glu/Lys/Ala (DEKA)，位于每个重复相应的SF位点，负责钠离子选择性。III-IV连接体包含Ile/Phe/Met (IFM)基序，这对于Nav通道的快速失活至关重要。疏水簇的诱变可以完全消除这种快速失活。研究结果 02 Nav通道是天然毒素和临床药物的主要靶点。本文综述了近年来Nav通道在与毒素和药物复合物中的结构进展。这些结构不仅增强了研究人员对配体调节机制和Nav通道结构药理学的掌握，而且还为人工智能(人工智能)药物发现提供了宝贵的训练数据库。 Nav通道在与特定配体结合时表现出构象动力学。一些配体以状态依赖的方式绑定到Nav通道。例如，尽管多次尝试，利多卡因的密度仍然是不可见的，而Funapide抑制剂和DSP-2230的分辨率是有限的。一个可能的原因是这些配体可能倾向于尚未被分解的不同状态。因此，获取Nav通道在静息状态等不同状态下的结构，对于药物的发现是必不可少的。为了实现这一目标，研究人员确定了Nav1.7-M11的结构，其中包含11个合理引入的点突变。对Nav1.7-M11的结构分析表明，VSDI为完全向下构象，而VSDII则处于中间状态。然而，VSDIII和VSDIV仍处于“上”构象，IFM基序仍与快速失活受体位点结合。尽管在Nav1.7-M11与野生型通道之间发生了剧烈的构象变化，但静止状态下的Nav通道结构仍然大致相同。值得注意的是，构象动力学超出了目前人工智能结构预测的能力。因此，获得与配体配合物不同状态下Nav通道的实验结构对于合理设计药物至关重要。同时，建立一个新的基于结构的命名体系来更好地描述Nav通道上不同的可药物位点是很重要的。这里描述的命名系统可以作为一个起点，将来可能会进行修改和优化。 Nav通道的结构和一般工作机制概述研究结论 03 综上，在这篇综述中，重点介绍了Nav通道的结构药理学的最新进展，这对未来合理的药物开发提供了重要的见解。参考资料： https://doi.org/10.1080/19336950.2023.2287832 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。热门·直播/活动 🕓 北京｜12月19日-20日 ▶第四届单细胞测序技术应用研讨会暨单细胞&空间组学研讨会（日程稍后公布）点击对应文字查看详情

100 项与 DSP-2230 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	DSP-2230	-	-

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
疼痛	临床2期	日本	Alphanavi Pharma KK初创企业	2020-12-30
神经痛	临床2期	英国	Sumitomo Pharma Co., Ltd.	-
神经痛	临床2期	日本	Sumitomo Pharma Co., Ltd.	-
神经痛	临床2期	美国	Sumitomo Pharma Co., Ltd.	-