N2-(2-bromophenyl)-5-chloro-N4-methylpyrimidine-2,4-diamine | 1379676-45-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N2-(2-bromophenyl)-5-chloro-N4-methylpyrimidine-2,4-diamine
• 英文别名: 2-N-(2-bromophenyl)-5-chloro-4-N-methylpyrimidine-2,4-diamine
• CAS: 1379676-45-5
• 化学式: C₁₁H₁₀BrClN₄
• 分子量: 313.584
• InChiKey: BDPAGGPRSHCHGI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  49.8
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  2,5-二氯-N-甲基嘧啶-4-胺 、 2-溴苯胺 以 正丁醇 为溶剂， 反应 0.33h， 生成 N2-(2-bromophenyl)-5-chloro-N4-methylpyrimidine-2,4-diamine
  参考文献：
  名称：

  Discovery of Selective LRRK2 Inhibitors Guided by Computational Analysis and Molecular Modeling

  摘要：

  Mutations in the genetic sequence of leucine-rich repeat kinase 2 (LRRK2) have been linked to increased LRRK2 activity and risk for the development of Parkinson's disease (PD). Potent, and selective small molecules capable of inhibiting the kinase activity of LARK2 will be important tools for establishing a link between the kinase activity of LRRK2 and PD. In the absence of LRRK2 kinase domain crystal structures, a LRRK2 homology model was developed that provided robust guidance in the hit-to-lead optimization of small molecule LRRK2 inhibitors. Through a combination of molecular modeling, sequence analysis, and matched molecular pair (MMP) activity cliff analysis, a potent and selective lead inhibitor was discovered. The selectivity of this compound could be understood using the LRRK2 homology model, and application of this learning to a series of 2,4-diaminopyrimidine inhibitors in a scaffold hopping exercise led to the identification of highly potent and selective LRRK2 inhibitors that were also brain penetrable.

  DOI：

  10.1021/jm300452p

文献信息

• Discovery of Selective LRRK2 Inhibitors Guided by Computational Analysis and Molecular Modeling
  作者：Huifen Chen、Bryan K. Chan、Jason Drummond、Anthony A. Estrada、Janet Gunzner-Toste、Xingrong Liu、Yichin Liu、John Moffat、Daniel Shore、Zachary K. Sweeney、Thuy Tran、Shumei Wang、Guiling Zhao、Haitao Zhu、Daniel J. Burdick

  DOI：10.1021/jm300452p

  日期：2012.6.14

  Mutations in the genetic sequence of leucine-rich repeat kinase 2 (LRRK2) have been linked to increased LRRK2 activity and risk for the development of Parkinson's disease (PD). Potent, and selective small molecules capable of inhibiting the kinase activity of LARK2 will be important tools for establishing a link between the kinase activity of LRRK2 and PD. In the absence of LRRK2 kinase domain crystal structures, a LRRK2 homology model was developed that provided robust guidance in the hit-to-lead optimization of small molecule LRRK2 inhibitors. Through a combination of molecular modeling, sequence analysis, and matched molecular pair (MMP) activity cliff analysis, a potent and selective lead inhibitor was discovered. The selectivity of this compound could be understood using the LRRK2 homology model, and application of this learning to a series of 2,4-diaminopyrimidine inhibitors in a scaffold hopping exercise led to the identification of highly potent and selective LRRK2 inhibitors that were also brain penetrable.