KB-R7943甲磺酰酸盐 | 182004-65-5

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: KB-R7943甲磺酰酸盐
• 中文别名: S-[4-[(4-硝基苄基)氧代]苯乙基]异硫脲甲磺酸盐；KB-R7943甲磺酸盐；2-[2-[4-(4-硝基苄氧基)苯基]乙基]异硫脲甲烷磺；KB-R7943 甲磺酰酸盐
• 英文名称: 2-[2-[4-(4-Nitrobenzyloxy)phenyl]ethyl]isothiourea mesylate
• 英文别名: methanesulfonic acid;2-[4-[(4-nitrophenyl)methoxy]phenyl]ethyl carbamimidothioate
• CAS: 182004-65-5
• 化学式: C17H21N3O6S2
• mdl: MFCD00952138
• 分子量: 427.5
• InChiKey: WGIKEBHIKKWJLG-UHFFFAOYSA-N

物化性质

• 熔点：
  >214°C (dec.)
• 溶解度：
  溶于DMSO（高达50mg/ml）。

计算性质

• 辛醇/水分配系数(LogP)：
  3.83
• 重原子数：
  28
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.235
• 拓扑面积：
  193
• 氢给体数：
  3
• 氢受体数：
  8

安全信息

• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

制备方法与用途

生物活性

KB-R7943 mesylate 是一种 Na+/Ca2+ 交换体 (NCXrev) 反向抑制剂，其 IC50 值为 5.7±2.1 µM。该化合物通过激活 JNK 通路和抑制自噬通量来诱导癌细胞死亡。

靶点

• IC50: 5.7±2.1 µM (Na+ /Ca2+ exchanger)

体外研究

KB-R7943 mesylate 可阻断 NMDAR 介导的离子电流，抑制 NMDA 引起的胞质钙离子增加（IC50 = 13.4±3.6 µM），但加速谷氨酸处理神经元中的钙失调和线粒体去极化。KB-R7943 可以在不依赖钙的情况下使线粒体去极化，并且抑制由 2,4-二硝基苯酚刺激的培养神经元呼吸（IC50 = 11.4±2.4 µM）。此外，除了 NCXrev 外，KB-R7943 剂量依赖性并可逆地阻断 NMDA 引起的离子电流。其对 NMDA 引起的钙浓度增加（[Ca2+]c）抑制表现出剂量依赖性且 IC50 = 13.4±3.6 µM，这与电生理学实验中观察到的 NMDA 受体抑制一致。

预处理有 wt RyR1 的 HEK 293 细胞（用 KB-R7943 [10 μM, 10 min] 溶解在基质灌流液中），对咖啡因诱导的钙释放反应显著减弱。与 0.5 mM 和 0.75 mM 相比，KB-R7943 对 1 mM 咖啡因引起的钙释放抑制作用更为明显（分别为 60%、58% 和 37%，p<0.05）。

此外，KB-R7943 在膜去极化时可剂量依赖性地抑制 I hERG 和原生的 I Kr，IC50 值分别约为 89 nM 和 120 nM。在去极化电压命令从 +20 mV 跟踪到 -40 mV 后的电流尾部。IhERG 抑制表现出时间和电压依赖性，但对失活通道和激活通道没有偏好。

文献信息

• Combination therapy involving a sodium-hydrogen exchanger type 1 or NHE-1 inhibitor for use in treatment of ischemia
  申请人：Pfizer Products Inc.

  公开号：EP1226830A2

  公开（公告）日：2002-07-31

  The invention provdes methods of reducing tissue damage resulting from ischemia which comprise administering to a mammal in need of such reduction an effective amount of a combination, or a pharmaceutical composition comprising such combination, of an NHE-1 inhibitor and a second compound selected from the group consisting of: (a) a complement modulator, (b) a metabolic modulator, (c) an anti-apoptotic agent, (d) a nitric oxide synthase-related agent, and (e) an enzyme/protein modulator. The invention further provides pharmaceutical compositions comprising an amount of an NHE-1 inhibitor; an amount of a second compound selected from the group consisting of (a) a complement modulator, (b) a metabolic modulator, (c) an anti-apoptotic agent, (d) a nitric oxide synthase-related agent, and an enzyme/protein modulator selected from the group consisting of a protein kinase C activator, an endothelin converting enzyme inhibitor, a thrombin-activatable fibrinolysis inhibitor (TAFI) inhibitor, an activated thrombin-activatable fibrinolysis inhibitor (TAFIa) inhibitor, a Na+/Ca+2 exchanger isoform-1 (NCX-1) inhibitor, and a poly (ADP ribose) synthetase (PARS/PARP) inhibitor; and, preferably, a pharmaceutically acceptable pharmaceutically acceptable carrier, vehicle, or diluent. The invention further provides kits comprising an amount of a sodium-hydrogen exchanger type-1 inhibitor, and a pharmaceutically acceptable carrier, vehicle, or diluent in a first unit dosage form; an amount of a second compound selected from the group consisting of (a) a complement modulator, (b) a metabolic modulator, (c) an anti-apoptotic agent, (d) a nitric oxide synthase-related agent, and (e) an enzyme/protein modulator selected from the group consisting of a protein kinase C activator, an endothelin converting enzyme inhibitor, a thrombin-activatable fibrinolysis inhibitor (TAFI) inhibitor, an activated thrombin-activatable fibrinolysis inhibitor (TAFIa) inhibitor, a Na+/Ca+2 exchanger isoform-1 (NCX-1) inhibitor, and a poly (ADP ribose) synthetase (PARS/PARP) inhibitor, and a pharmaceutically acceptable carrier, vehicle, or diluent in a second unit dosage form; and a container.

  本发明提供了减少缺血导致的组织损伤的方法，该方法包括向需要减少损伤的哺乳动物施用有效量的 NHE-1 抑制剂和选自以下组别的第二种化合物的组合或包含这种组合的药物组合物：(a) 补体调节剂，(b) 代谢调节剂，(c) 抗凋亡剂，(d) 一氧化氮合酶相关剂，和 (e) 酶/蛋白调节剂。本发明进一步提供了药物组合物，其中包含一定量的 NHE-1 抑制剂；一定量的选自以下组别的第二种化合物：(a) 补体调节剂；(b) 代谢调节剂；(c) 抗凋亡剂；(d) 一氧化氮合酶相关剂；以及选自以下组别的酶/蛋白调节剂：蛋白激酶 C 激活剂、内皮素转换酶抑制剂、凝血酶活化性纤维蛋白溶解抑制剂（TAFI）抑制剂、活化的凝血酶活化性纤维蛋白溶解抑制剂（TAFIa）抑制剂、Na+/Ca+2 交换异构体-1（NCX-1）抑制剂和多（ADP 核糖）合成酶（PARS/PARP）抑制剂；以及，优选药学上可接受的载体、载体或稀释剂。本发明进一步提供了包含一定量的钠-氢交换剂型-1 抑制剂和药学上可接受的载体、载体或稀释剂的试剂盒，试剂盒为第一单位剂型；一定量的选自以下组别的第二种化合物：(a) 补体调节剂；(b) 代谢调节剂；(c) 抗细胞凋亡剂；(d) 一氧化氮合酶相关剂；(e) 酶/蛋白调节剂，选自以下组别：蛋白激酶 C 激活剂；内皮素转换酶抑制剂；凝血酶激活的可凝血酶抑制剂、凝血酶活化性纤维蛋白溶解抑制剂（TAFI）抑制剂、活化的凝血酶活化性纤维蛋白溶解抑制剂（TAFIa）抑制剂、Na+/Ca+2 交换异构体-1（NCX-1）抑制剂和聚（ADP 核糖）合成酶（PARS/PARP）抑制剂，以及药学上可接受的载体、载体或稀释剂组成的组；以及一个容器。
• NOVEL POTASSIUM-DEPENDENT SODIUM-CALCIUM EXCHANGER
  申请人：YAMANOUCHI PHARMACEUTICAL CO. LTD.

  公开号：EP1526140A1

  公开（公告）日：2005-04-27

  A novel polypeptide, a polynucleotide encoding the polypeptide, an expression vector comprising the polynucleotide, a cell transfected by the expression vector, a method for producing the polypeptide, and a convenient screening system for obtaining a substance useful in treating cell injuries due to postischemic reperfusion or an inflammatory disease, are disclosed. The polypeptide is a potassium-dependent sodium-calcium exchanger expressed in peripheral leukocytes.

  本发明公开了一种新型多肽、一种编码该多肽的多核苷酸、一种包含该多核苷酸的表达载体、一种由该表达载体转染的细胞、一种生产该多肽的方法以及一种方便的筛选系统，该系统可用于获得一种可治疗因缺血后再灌注或炎症性疾病引起的细胞损伤的物质。 该多肽是一种在外周白细胞中表达的钾依赖性钠钙交换子。
• Na+/Mg2+ exchanger
  申请人：FBN - Leibniz-Institut für Nutztierbiologie

  公开号：EP2431386A1

  公开（公告）日：2012-03-21

  The invention relates to methods to identify new SLC41A1 functions at the cell, tissue, organ and organism level. In part, it is related to methods useful in (a) identifying molecules that bind SLC41A1 polypeptides, which (b) modulate SLC41A1 related Na+/Mg2+ exchanger activity or its cellular or tissue specific expression. Thus, the invention comprises SLC41A1 mutation libraries, SLC41A1 specific antibodies, their generation and finding as well as an inducible conditional SLC41A1 knock out mice model and inducible conditional knock out SLC41A1 cell lines.

  本发明涉及在细胞、组织、器官和机体水平鉴定 SLC41A1 新功能的方法。本发明部分涉及用于（a）鉴定结合 SLC41A1 多肽的分子，（b）调节与 SLC41A1 相关的 Na+/Mg2+ 交换器活性或其细胞或组织特异性表达的方法。 因此，本发明包括 SLC41A1 基因突变文库、SLC41A1 特异性抗体、它们的产生和发现以及可诱导的条件性 SLC41A1 基因敲除小鼠模型和可诱导的条件性基因敲除 SLC41A1 细胞系。
• COMBINATION THERAPY
  申请人：——

  公开号：US20020099075A1

  公开（公告）日：2002-07-25

  The invention provdes methods of reducing tissue damage resulting from ischemia which comprise administering to a mammal in need of such reduction an effective amount of a combination, or a pharmaceutical composition comprising such combination, of an NHE-1 inhibitor and a second compound selected from the group consisting of: (a) a complement modulator, (b) a metabolic modulator, (c) an anti-apoptotic agent, (d) a nitric oxide synthase-related agent, and (e) an enzyme/protein modulator. The invention further provides pharmaceutical compositions comprising an amount of an NHE-1 inhibitor; an amount of a second compound selected from the group consisting of (a) a complement modulator, (b) a metabolic modulator, (c) an anti-apoptotic agent, (d) a nitric oxide synthase-related agent, and an enzyme/protein modulator selected from the group consisting of a protein kinase C activator, an endothelin converting enzyme inhibitor, a tissue-activated fibrinolytic inhibitor (TAFI), a Na + /Ca +2 exchanger isoform-1 (NCX-1) inhibitor, and a poly (ADP ribose) synthetase (PARS/PARP) inhibitor; and, preferably, a pharmaceutically acceptable pharmaceutically acceptable carrier, vehicle, or diluent. The invention further provides kits comprising an amount of a sodium-hydrogen exchanger type-1 inhibitor, and a pharmaceutically acceptable carrier, vehicle, or diluent in a first unit dosage form; an amount of a second compound selected from the group consisting of (a) a complement modulator, (b) a metabolic modulator, (c) an anti-apoptotic agent, (d) a nitric oxide synthase-related agent, and (e) an enzyme/protein modulator selected from the group consisting of a protein kinase C activator, an endothelin converting enzyme inhibitor, a tissue-activated fibrinolytic inhibitor (TAFI), a Na + /Ca +2 exchanger isoform-1 (NCX-1) inhibitor, and a poly (ADP ribose) synthetase (PARS/PARP) inhibitor, and a pharmaceutically acceptable carrier, vehicle, or diluent in a second unit dosage form; and a container.

  本发明提供了减少缺血导致的组织损伤的方法，该方法包括向需要减少损伤的哺乳动物施用有效量的NHE-1抑制剂和选自以下组的第二种化合物的组合或包含这种组合的药物组合物：(a)补体调节剂，(b)代谢调节剂，(c)抗细胞凋亡剂，(d)一氧化氮合酶相关剂，和(e)酶/蛋白调节剂。本发明进一步提供了药物组合物，该药物组合物包含一定量的 NHE-1 抑制剂；一定量的选自以下组别的第二种化合物：(a) 补体调节剂；(b) 代谢调节剂；(c) 抗细胞凋亡剂；(d) 一氧化氮合酶相关剂；以及选自以下组别的酶/蛋白质调节剂：蛋白激酶 C 激活剂、内皮素转换酶抑制剂、组织活化纤溶抑制剂 (TAFI)、Na. 加 /Ca 2 交换剂同工酶-1（NCX-1）抑制剂和聚（ADP 核糖）合成酶（PARS/PARP）抑制剂；以及，优选药学上可接受的载体、载体或稀释剂。本发明进一步提供了包含一定量的钠-氢交换机 1 型抑制剂和药学上可接受的载体、载体或稀释剂的试剂盒，试剂盒为第一单位剂型；一定量的选自以下组别的第二种化合物：(a) 补体调节剂；(b) 代谢调节剂；(c) 抗凋亡剂；(d) 一氧化氮合酶相关剂；(e) 酶/蛋白调节剂，选自以下组别：蛋白激酶 C 激活剂、内皮素转换酶抑制剂、组织活化纤溶抑制剂（TAFI）、Na 加 /Ca 2 交换剂同工酶-1（NCX-1）抑制剂和聚（ADP 核糖）合成酶（PARS/PARP）抑制剂，以及药学上可接受的载体、载体或稀释剂的第二单位剂型；和容器。
• Novel potassium-dependent sodium-calcium exchanger
  申请人：Nozawa Katsura

  公开号：US20050119173A1

  公开（公告）日：2005-06-02

  A novel polypeptide, a polynucleotide encoding the polypeptide, an expression vector comprising the polynucleotide, a cell transfected by the expression vector, a method for producing the polypeptide, and a convenient screening system for obtaining a substance useful in treating cell injuries due to postischemic reperfusion or an inflammatory disease, are disclosed. The polypeptide is a potassium-dependent sodium-calcium exchanger expressed in peripheral leukocytes.

  本发明公开了一种新型多肽、一种编码该多肽的多核苷酸、一种包含该多核苷酸的表达载体、一种由该表达载体转染的细胞、一种生产该多肽的方法以及一种方便的筛选系统，该系统可用于获得一种可治疗因缺血后再灌注或炎症性疾病引起的细胞损伤的物质。该多肽是一种在外周白细胞中表达的钾依赖性钠钙交换子。