2-(benzyloxy)-5-(4-(2-methoxyethyl)piperazin-1-yl)-N-(pyridazin-4-yl)benzamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 2-(benzyloxy)-5-(4-(2-methoxyethyl)piperazin-1-yl)-N-(pyridazin-4-yl)benzamide
• 英文别名: 5-[4-(2-methoxyethyl)piperazin-1-yl]-2-phenylmethoxy-N-pyridazin-4-ylbenzamide
• 化学式: C₂₅H₂₉N₅O₃
• 分子量: 447.537
• InChiKey: AJKHEQUQNWCJNL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  33
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  79.8
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  5-溴水杨酸 在 potassium fluoride 、 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 potassium acetate 、 copper diacetate 、 potassium carbonate 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 sodium iodide 、 sodium hydroxide 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 10.0h， 生成 2-(benzyloxy)-5-(4-(2-methoxyethyl)piperazin-1-yl)-N-(pyridazin-4-yl)benzamide
  参考文献：
  名称：

  5-Substituted-N-pyridazinylbenzamides as potent and selective LRRK2 inhibitors: Improved brain unbound fraction enables efficacy

  摘要：

  We describe the discovery and optimization of 5-substituted-N-pyridazinylbenzamide derivatives as potent and selective LRRK2 inhibitors. Extensive SAR studies led to the identification of compounds 18 and 23, which demonstrated good in vitro pharmacokinetic profile and excellent selectivity over 140 other kinases. Both compounds demonstrated high unbound fractions in both blood and brain. Compound 18 proved to be brain penetrant, and the high unbound fraction of compound 18 in brain enabled its in vivo efficacy in CNS, wherein a significant inhibition of LRRK2 Ser935 phosphorylation was observed in rat brain following intravenous infusion at 5 mg/kg/h.

  DOI：

  10.1016/j.bmcl.2018.11.054

文献信息

• 5-Substituted-N-pyridazinylbenzamides as potent and selective LRRK2 inhibitors: Improved brain unbound fraction enables efficacy
  作者：Xiao Ding、Luigi Piero Stasi、Xuedong Dai、Kai Long、Cheng Peng、Baowei Zhao、Hailong Wang、Changhui Sun、Huan Hu、Zehong Wan、Karamjit S. Jandu、Oliver J. Philps、Yan Chen、Lizhen Wang、Qian Liu、Colin Edge、Yi Li、Kelly Dong、Xiaoming Guan、F. David Tattersall、Alastair D. Reith、Feng Ren

  DOI：10.1016/j.bmcl.2018.11.054

  日期：2019.1

  We describe the discovery and optimization of 5-substituted-N-pyridazinylbenzamide derivatives as potent and selective LRRK2 inhibitors. Extensive SAR studies led to the identification of compounds 18 and 23, which demonstrated good in vitro pharmacokinetic profile and excellent selectivity over 140 other kinases. Both compounds demonstrated high unbound fractions in both blood and brain. Compound 18 proved to be brain penetrant, and the high unbound fraction of compound 18 in brain enabled its in vivo efficacy in CNS, wherein a significant inhibition of LRRK2 Ser935 phosphorylation was observed in rat brain following intravenous infusion at 5 mg/kg/h.