5-bromonaphtho[1,2-d]thiazol-2-amine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 萘并噻唑类
• 英文名称: 5-bromonaphtho[1,2-d]thiazol-2-amine
• 英文别名: 5-Bromobenzo[e][1,3]benzothiazol-2-amine；5-bromobenzo[e][1,3]benzothiazol-2-amine
• 化学式: C₁₁H₇BrN₂S
• 分子量: 279.16
• InChiKey: JGZLSXKASSIZRR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  15
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  67.2
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  安妥 在 氯仿 、 溴 作用下， 生成 5-bromonaphtho[1,2-d]thiazol-2-amine
  参考文献：
  名称：

  Desai et al., Journal of the Chemical Society, 1936, p. 1668,1670

  摘要：

  DOI：

文献信息

• New Positive Ca²⁺-Activated K⁺ Channel Gating Modulators with Selectivity for K_Ca3.1
  作者：Nichole Coleman、Brandon M. Brown、Aida Oliván-Viguera、Vikrant Singh、Marilyn M. Olmstead、Marta Sofia Valero、Ralf Köhler、Heike Wulff

  DOI：10.1124/mol.114.093286

  日期：2014.9

  Small-conductance (KCa2) and intermediate-conductance (KCa3.1) calcium-activated K+ channels are voltage-independent and share a common calcium/calmodulin-mediated gating mechanism. Existing positive gating modulators like EBIO, NS309, or SKA-31 activate both KCa2 and KCa3.1 channels with similar potency or, as in the case of CyPPA and NS13001, selectively activate KCa2.2 and KCa2.3 channels. We performed a structure-activity relationship (SAR) study with the aim of optimizing the benzothiazole pharmacophore of SKA-31 toward KCa3.1 selectivity. We identified SKA-111 (5-methylnaphtho[1,2- d ]thiazol-2-amine), which displays 123-fold selectivity for KCa3.1 (EC50 111 ± 27 nM) over KCa2.3 (EC50 13.7 ± 6.9 μ M), and SKA-121 (5-methylnaphtho[2,1- d ]oxazol-2-amine), which displays 41-fold selectivity for KCa3.1 (EC50 109 nM ± 14 nM) over KCa2.3 (EC50 4.4 ± 1.6 μ M). Both compounds are 200- to 400-fold selective over representative KV (KV1.3, KV2.1, KV3.1, and KV11.1), NaV (NaV1.2, NaV1.4, NaV1.5, and NaV1.7), as well as CaV1.2 channels. SKA-121 is a typical positive-gating modulator and shifts the calcium-concentration response curve of KCa3.1 to the left. In blood pressure telemetry experiments, SKA-121 (100 mg/kg i.p.) significantly lowered mean arterial blood pressure in normotensive and hypertensive wild-type but not in KCa3.1−/− mice. SKA-111, which was found in pharmacokinetic experiments to have a much longer half-life and to be much more brain penetrant than SKA-121, not only lowered blood pressure but also drastically reduced heart rate, presumably through cardiac and neuronal KCa2 activation when dosed at 100 mg/kg. In conclusion, with SKA-121, we generated a KCa3.1-specific positive gating modulator suitable for further exploring the therapeutical potential of KCa3.1 activation.

  小电导（KCa2）和中电导（KCa3.1）钙激活 K+ 通道与电压无关，具有共同的钙/钙调素介导的门控机制。现有的正门控调节剂（如 EBIO、NS309 或 SKA-31）能以类似的效力激活 KCa2 和 KCa3.1 通道，或者像 CyPPA 和 NS13001 那样选择性地激活 KCa2.2 和 KCa2.3 通道。我们进行了一项结构-活性关系 (SAR) 研究，目的是优化 SKA-31 的苯并噻唑药理结构，使其具有 KCa3.1 选择性。我们确定了 SKA-111（5-甲基萘并[1,2-d]噻唑-2-胺），它对 KCa3.1 的选择性（EC50 111 ± 27 nM）是 KCa2.3 的 123 倍（EC50 13.7 ± 6.9 μ M）和 SKA-121 （5-甲基萘并[2,1-d]恶唑-2-胺），后者对 KCa3.1 的选择性（EC50 109 nM ± 14 nM）是 KCa2.3 的选择性（EC50 4.4 ± 1.6 μ M）的 41 倍。这两种化合物对代表性 KV（KV1.3、KV2.1、KV3.1 和 KV11.1）、NaV（NaV1.2、NaV1.4、NaV1.5 和 NaV1.7）以及 CaV1.2 通道的选择性均为 200 到 400 倍。SKA-121 是一种典型的正通路调节剂，能使 KCa3.1 的钙离子浓度反应曲线向左移动。在血压遥测实验中，SKA-121（100 mg/kg i.p.）能显著降低血压正常和高血压野生型小鼠的平均动脉血压，但不能降低 KCa3.1-/- 小鼠的平均动脉血压。在药代动力学实验中发现，SKA-111 的半衰期比 SKA-121 长得多，对大脑的渗透性也更强，当剂量为 100 毫克/公斤时，SKA-121 不仅能降低血压，还能大幅降低心率，这可能是通过激活心脏和神经元 KCa2 实现的。总之，我们利用 SKA-121 生成了一种 KCa3.1 特异性正向门控调节剂，适合进一步探索 KCa3.1 激活的治疗潜力。
• Selective activators of the intermediate conductance CA2+activated K+ channel KCa3.1 and their methods of use
  申请人：The Regents of the University of California

  公开号：US11173146B2

  公开（公告）日：2021-11-16

  Benzoxazole and indole type KCa3.1 activators as well as the therapeutic uses of such compounds in human or animal subjects and their use in ex vivo preservation of organs or tissues.

  苯并噁唑和吲哚类 KCa3.1 激活剂，以及此类化合物在人类或动物身上的治疗用途及其在器官或组织体外保存中的用途。
• Desai et al., Journal of the Chemical Society, 1936, p. 1668,1670
  作者：Desai et al.

  DOI：——

  日期：——
• SELECTIVE ACTIVATORS OF THE INTERMEDIATE CONDUCTANCE CA2+ACTIVATED K+ CHANNEL KCa3.1 AND THEIR METHODS OF USE
  申请人：The Regents of the University of California

  公开号：US20170056376A1

  公开（公告）日：2017-03-02

  Benzoxazole and indole type KCa3.1 activators as well as the therapeutic uses of such compounds in human or animal subjects and their use in ex vivo preservation of organs or tissues.
• [EN] SELECTIVE ACTIVATORS OF THE INTERMEDIATE CONDUCTANCE CA2+-ACTIVATED K+ CHANNEL KCA3.1 AND THEIR METHODS OF USE<br/>[FR] ACTIVATEURS SÉLECTIFS DES CANAUX K+ (KCA3.1) ACTIVÉS PAR LE CA2+ À CONDUCTANCE INTERMÉDIAIRE, ET LEURS MÉTHODES D'UTILISATION
  申请人：UNIV CALIFORNIA

  公开号：WO2015164816A2

  公开（公告）日：2015-10-29

  Benzoxazole and indole type KCa3.1 activators as well as the therapeutic uses of such compounds in human or animal subjects and their use in ex vivo preservation of organs or tissues.