(4-bromo-1-methyl-1H-pyrazol-3-yl)-(3-hydroxy-3-trifluoromethyl-3,3a,4,5,6,7-hexahydroindazol-2-yl)methanone

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: (4-bromo-1-methyl-1H-pyrazol-3-yl)-(3-hydroxy-3-trifluoromethyl-3,3a,4,5,6,7-hexahydroindazol-2-yl)methanone
• 英文别名: [(3S,3aR)-3-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-3aH-indazol-2-yl]-(4-bromo-1-methylpyrazol-3-yl)methanone
• 化学式: C₁₃H₁₄BrF₃N₄O₂
• 分子量: 395.179
• InChiKey: DZHGRMGZNAUJHL-KRTXAFLBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  23
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  70.7
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  1-甲基-4-硝基-3-吡唑羧酸甲酯 在 哌啶 、 亚硝酸特丁酯 、 palladium 10% on activated carbon 、 氢气 、 一水合肼 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 5.0~60.0 ℃ 、2.0 MPa 条件下， 反应 11.25h， 生成 (4-bromo-1-methyl-1H-pyrazol-3-yl)-(3-hydroxy-3-trifluoromethyl-3,3a,4,5,6,7-hexahydroindazol-2-yl)methanone
  参考文献：
  名称：

  Fused 3-Hydroxy-3-trifluoromethylpyrazoles Inhibit Mutant Huntingtin Toxicity

  摘要：

  Here, we describe the selection and optimization of a chemical series active in both a full-length and a fragment-based Huntington's disease (HD) assay. Twenty-four thousand small molecules were screened in a phenotypic HD assay, identifying a series of compounds bearing a 3-hydroxy-3-trifluoromethylpyrazole moiety as able to revert the toxicity induced by full-length mutant Htt by up to 50%. A chemical exploration around the series led to the identification of compound 4f, which demonstrated to be active in a Htt171-82Qrat primary striatal neuron assay and a PC12-Exon-1 based assay. This compound was selected for testing in R6/2 mice, in which it was well-tolerated and showed a positive effect on body weight and a positive trend in preventing ventricular volume enlargment. These studies provide strong rationale for further testing the potential benefits of 3-hydroxy-3-trifluoromethylpyrazoles in treating HD.

  DOI：

  10.1021/ml400251g