N²-((6S)-4,6-dimethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]-oxazin-3-yl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine | 1536199-93-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: N²-((6S)-4,6-dimethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]-oxazin-3-yl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine
• 英文别名: 2-N-[(6S)-4,6-dimethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl]-4-N-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine
• CAS: 1536199-93-5
• 化学式: C₁₄H₁₇F₃N₆O
• 分子量: 342.324
• InChiKey: HVPGKPCGQMAXGL-JAMMHHFISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  76.9
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  在 sodium hydride 、 一水合肼 、 叔丁醇 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 16.25h， 生成 N²-((6S)-4,6-dimethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]-oxazin-3-yl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine
  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

文献信息

• Discovery of Highly Potent, Selective, and Brain-Penetrant Aminopyrazole Leucine-Rich Repeat Kinase 2 (LRRK2) Small Molecule Inhibitors
  作者：Anthony A. Estrada、Bryan K. Chan、Charles Baker-Glenn、Alan Beresford、Daniel J. Burdick、Mark Chambers、Huifen Chen、Sara L. Dominguez、Jennafer Dotson、Jason Drummond、Michael Flagella、Reina Fuji、Andrew Gill、Jason Halladay、Seth F. Harris、Timothy P. Heffron、Tracy Kleinheinz、Donna W. Lee、Claire E. Le Pichon、Xingrong Liu、Joseph P. Lyssikatos、Andrew D. Medhurst、John G. Moffat、Kevin Nash、Kimberly Scearce-Levie、Zejuan Sheng、Daniel G. Shore、Susan Wong、Shuo Zhang、Xiaolin Zhang、Haitao Zhu、Zachary K. Sweeney

  DOI：10.1021/jm401654j

  日期：2014.2.13

  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.