4-(3-(cis-2,6-dimethylmorpholino)isothiazolo[4,3-b]pyridin-6-yl)-2-methoxyaniline

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 4-(3-(cis-2,6-dimethylmorpholino)isothiazolo[4,3-b]pyridin-6-yl)-2-methoxyaniline
• 英文别名: 6-(4-amino-3-methoxyphenyl)-3-(cis-2,6-dimethylmorpholino)isothiazolo[4,3-b]pyridine；GAK inhibitor 12r；4-[3-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-[1,2]thiazolo[4,3-b]pyridin-6-yl]-2-methoxyaniline
• 化学式: C₁₉H₂₂N₄O₂S
• 分子量: 370.475
• InChiKey: VOFMQYIALBSDFI-TXEJJXNPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  26
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  102
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  4-(3-(cis-2,6-dimethylmorpholino)isothiazolo[4,3-b]pyridin-6-yl)-2-methoxyaniline 、 环丙基甲酰氯 在 trialkylamine 作用下， 以 二氯甲烷 为溶剂， 以79%的产率得到6-(3-methoxy-4-cyclopropylamidophenyl)-3-(cis-2,6-dimethylmorpholino)isothiazolo[4,3-b]pyridine
  参考文献：
  名称：

  异噻唑并[4,3-b]吡啶的吡啶部分作为靶向细胞周期蛋白G相关激酶的抗病毒剂的结构活性关系研究。

  摘要：

  以前，我们报道了3,6-二取代异噻唑并[4,3-b]吡啶的发现，它是有效的和选择性的细胞周期蛋白G相关激酶（GAK）抑制剂，具有有希望的抗病毒活性。在该手稿中，结构-活性关系研究扩展到合成具有吡啶部分修饰的异噻唑并[4,3-b]吡啶。这项工作导致发现了在位置5具有3,4-二甲氧基苯基残基的异噻唑并[4,3-b]吡啶衍生物，该衍生物显示出低的纳摩尔GAK结合亲和力和抗登革热病毒的抗病毒活性。

  DOI：

  10.1016/j.bmc.2019.115188
• 作为产物：
  描述：

  5-溴-2-氰基-3-硝基吡啶 在 劳森试剂 、 四(三苯基膦)钯 、 氢溴酸 、 双氧水 、 铁粉 、 potassium carbonate 、 溶剂黄146 作用下， 以 1,4-二氧六环 、 甲醇 、 乙醇 、 水 为溶剂， 反应 27.17h， 生成 4-(3-(cis-2,6-dimethylmorpholino)isothiazolo[4,3-b]pyridin-6-yl)-2-methoxyaniline
  参考文献：
  名称：

  Optimization of Isothiazolo[4,3-b]pyridine-Based Inhibitors of Cyclin G Associated Kinase (GAK) with Broad-Spectrum Antiviral Activity

  摘要：

  There is an urgent need for strategies to combat dengue and other emerging viral infections. We reported that cyclin G-associated kinase (GAK), a cellular regulator of the clathrin-associated host adaptor proteins AP-1 and AP-2, regulates intracellular trafficking of multiple unrelated RNA viruses during early and late stages of the viral lifecycle. We also reported the discovery of potent, selective GAK inhibitors based on an isothiazolo[4,3-b]pyridine scaffold, albeit with moderate antiviral activity. Here, we describe our efforts leading to the discovery of novel isothiazolo[4,3-b]pyridines that maintain high GAK affinity and selectivity. These compounds demonstrate improved in vitro activity against dengue virus, including in human primary dendritic cells, and efficacy against the unrelated Ebola and chikungunya viruses. Moreover, inhibition of GAK activity was validated as an important mechanism of antiviral action of these compounds. These findings demonstrate the potential utility of a GAK-targeted broad-spectrum approach for combating currently untreatable emerging viral infections.

  DOI：

  10.1021/acs.jmedchem.8b00613

文献信息

• Structure-activity relationship study of the pyridine moiety of isothiazolo[4,3-b]pyridines as antiviral agents targeting cyclin G-associated kinase
  作者：Belén Martinez-Gualda、Szu-Yuan Pu、Mathy Froeyen、Piet Herdewijn、Shirit Einav、Steven De Jonghe

  DOI：10.1016/j.bmc.2019.115188

  日期：2020.1

  promising antiviral activity. In this manuscript, the structure-activity relationship study was expanded to synthesis of isothiazolo[4,3-b]pyridines with modifications of the pyridine moiety. This effort led to the discovery of an isothiazolo[4,3-b]pyridine derivative with a 3,4-dimethoxyphenyl residue at position 5 that displayed low nanomolar GAK binding affinity and antiviral activity against dengue

  以前，我们报道了3,6-二取代异噻唑并[4,3-b]吡啶的发现，它是有效的和选择性的细胞周期蛋白G相关激酶（GAK）抑制剂，具有有希望的抗病毒活性。在该手稿中，结构-活性关系研究扩展到合成具有吡啶部分修饰的异噻唑并[4,3-b]吡啶。这项工作导致发现了在位置5具有3,4-二甲氧基苯基残基的异噻唑并[4,3-b]吡啶衍生物，该衍生物显示出低的纳摩尔GAK结合亲和力和抗登革热病毒的抗病毒活性。
• Optimization of Isothiazolo[4,3-<i>b</i>]pyridine-Based Inhibitors of Cyclin G Associated Kinase (GAK) with Broad-Spectrum Antiviral Activity
  作者：Szu-Yuan Pu、Randy Wouters、Stanford Schor、Jef Rozenski、Rina Barouch-Bentov、Laura I. Prugar、Cecilia M. O’Brien、Jennifer M. Brannan、John M. Dye、Piet Herdewijn、Steven De Jonghe、Shirit Einav

  DOI：10.1021/acs.jmedchem.8b00613

  日期：2018.7.26

  There is an urgent need for strategies to combat dengue and other emerging viral infections. We reported that cyclin G-associated kinase (GAK), a cellular regulator of the clathrin-associated host adaptor proteins AP-1 and AP-2, regulates intracellular trafficking of multiple unrelated RNA viruses during early and late stages of the viral lifecycle. We also reported the discovery of potent, selective GAK inhibitors based on an isothiazolo[4,3-b]pyridine scaffold, albeit with moderate antiviral activity. Here, we describe our efforts leading to the discovery of novel isothiazolo[4,3-b]pyridines that maintain high GAK affinity and selectivity. These compounds demonstrate improved in vitro activity against dengue virus, including in human primary dendritic cells, and efficacy against the unrelated Ebola and chikungunya viruses. Moreover, inhibition of GAK activity was validated as an important mechanism of antiviral action of these compounds. These findings demonstrate the potential utility of a GAK-targeted broad-spectrum approach for combating currently untreatable emerging viral infections.