2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)-N-(2,2,2-trifluoroethyl)propanamide | 1536200-51-7

• 分子结构分类: 有机化合物 - 有机1,3-偶极化合物 - 烯丙基型1,3-偶极有机化合物
• 英文名称: 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)-N-(2,2,2-trifluoroethyl)propanamide
• CAS: 1536200-51-7
• 化学式: C₁₀H₁₃F₃N₄O₃
• 分子量: 294.233
• InChiKey: HXWWZEXZXFBVKO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.51
• 重原子数：
  20.0
• 可旋转键数：
  4.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  90.06
• 氢给体数：
  1.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)-N-(2,2,2-trifluoroethyl)propanamide 在 palladium 10% on activated carbon 、 氢气 、 三乙胺 作用下， 以 甲醇 、 正丁醇 为溶剂， 120.0 ℃ 、101.33 kPa 条件下， 反应 2.0h， 生成 2-methy l - 2 - ( 3 - m e t h y l - 4 - ( ( 4 - (methylamino ) - 5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-N-(2,2,2-trifluoroethyl)propanamide
  参考文献：
  名称：

  Discovery of Highly Potent, Selective, and Brain-Penetrant Aminopyrazole Leucine-Rich Repeat Kinase 2 (LRRK2) Small Molecule Inhibitors

  摘要：

  Leucine-rich repeat kinase 2 (LRRK2) has drawn significant interest in the neuroscience research community because it is one of the most compelling targets for a potential disease-modifying Parkinson's disease therapy. Herein, we disclose structurally diverse small molecule inhibitors suitable for assessing the implications of sustained in vivo LARK2 inhibition. Using previously reported aminopyrazole 2 as a lead molecule, we were able to engineer structural modifications in the solvent-exposed region of the ATP-binding site that significantly improve human hepatocyte stability, rat free brain exposure, and CYP inhibition and induction liabilities. Disciplined application of established optimal CNS design parameters culminated in the rapid identification of GNE-0877 (11) and GNE-9605 (20) as highly potent and selective LRRK2 inhibitors. The demonstrated metabolic stability, brain penetration across multiple species, and selectivity of these inhibitors support their use in preclinical efficacy and safety studies.

  DOI：

  10.1021/jm401654j
• 作为产物：
  描述：

  methyl 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanoate 在 草酰氯 、 lithium hydroxide 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 为溶剂， 反应 19.0h， 生成 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)-N-(2,2,2-trifluoroethyl)propanamide
  参考文献：
  名称：

  Discovery of Highly Potent, Selective, and Brain-Penetrant Aminopyrazole Leucine-Rich Repeat Kinase 2 (LRRK2) Small Molecule Inhibitors

  摘要：

  Leucine-rich repeat kinase 2 (LRRK2) has drawn significant interest in the neuroscience research community because it is one of the most compelling targets for a potential disease-modifying Parkinson's disease therapy. Herein, we disclose structurally diverse small molecule inhibitors suitable for assessing the implications of sustained in vivo LARK2 inhibition. Using previously reported aminopyrazole 2 as a lead molecule, we were able to engineer structural modifications in the solvent-exposed region of the ATP-binding site that significantly improve human hepatocyte stability, rat free brain exposure, and CYP inhibition and induction liabilities. Disciplined application of established optimal CNS design parameters culminated in the rapid identification of GNE-0877 (11) and GNE-9605 (20) as highly potent and selective LRRK2 inhibitors. The demonstrated metabolic stability, brain penetration across multiple species, and selectivity of these inhibitors support their use in preclinical efficacy and safety studies.

  DOI：

  10.1021/jm401654j