5-Amino-2-(2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-oxazole-4-carbonitrile | 1478983-19-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并二恶烷
• 英文名称: 5-Amino-2-(2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-oxazole-4-carbonitrile
• CAS: 1478983-19-5
• 化学式: C₁₂H₉N₃O₃
• mdl: MFCD23174770
• 分子量: 243.222
• InChiKey: DYMHGLFKSDMQCV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  18
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.166
• 拓扑面积：
  94.3
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  聚合甲醛 、 5-Amino-2-(2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-oxazole-4-carbonitrile 、 三氟乙酸 在 sodium methylate 、 sodium tetrahydroborate 作用下， 以 甲醇 、 水 、 乙腈 为溶剂， 反应 2.0h， 生成 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-(methylamino)oxazole-4-carbonitrile trifluoroacetate
  参考文献：
  名称：

  Potent and Selective Inhibitors of Human Reticulocyte 12/15-Lipoxygenase as Anti-Stroke Therapies

  摘要：

  A key challenge facing drug discovery today is variability of the drug target between species, such as with 12/15-lipoxygenase (12/15-LOX), which contributes to ischemic brain injury, but its human and rodent isozymes have different inhibitor specificities. In the current work, we have utilized a quantitative high-throughput (qHTS) screen to identify compound 1 (ML351), a novel chemotype for 12/15-LOX inhibition that has nanomolar potency (IC50 = 200 nM) against human 12/15-LOX and is protective against oxidative glutamate toxicity in mouse neuronal HT22 cells. In addition, it exhibited greater than 250-fold selectivity versus related LOX isozymes, was a mixed inhibitor, and did not reduce the active-site ferric ion. Lastly, 1 significantly reduced infarct size following permanent focal ischemia in a mouse model of ischemic stroke. As such, this represents the first report of a selective inhibitor of human 12/15-LOX with demonstrated in vivo activity in proof-of-concept mouse models of stroke.

  DOI：

  10.1021/jm401915r
• 作为产物：
  描述：

  2,3-二氢-1,4-苯并二噁烷-6-羧酸 、 对苯二磺酸氨基丙二酰丁氰 在 1-丙基磷酸酐 、 三乙胺 作用下， 以 乙酸乙酯 为溶剂， 反应 12.0h， 生成 5-Amino-2-(2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-oxazole-4-carbonitrile
  参考文献：
  名称：

  Potent and Selective Inhibitors of Human Reticulocyte 12/15-Lipoxygenase as Anti-Stroke Therapies

  摘要：

  A key challenge facing drug discovery today is variability of the drug target between species, such as with 12/15-lipoxygenase (12/15-LOX), which contributes to ischemic brain injury, but its human and rodent isozymes have different inhibitor specificities. In the current work, we have utilized a quantitative high-throughput (qHTS) screen to identify compound 1 (ML351), a novel chemotype for 12/15-LOX inhibition that has nanomolar potency (IC50 = 200 nM) against human 12/15-LOX and is protective against oxidative glutamate toxicity in mouse neuronal HT22 cells. In addition, it exhibited greater than 250-fold selectivity versus related LOX isozymes, was a mixed inhibitor, and did not reduce the active-site ferric ion. Lastly, 1 significantly reduced infarct size following permanent focal ischemia in a mouse model of ischemic stroke. As such, this represents the first report of a selective inhibitor of human 12/15-LOX with demonstrated in vivo activity in proof-of-concept mouse models of stroke.

  DOI：

  10.1021/jm401915r