(R)-2-chloro-7-ethyl-5-methyl-8-((R)-tetrahydrofuran-3-yl)-7,8-dihydropteridin-6(5H)-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 蝶啶及其衍生物
• 英文名称: (R)-2-chloro-7-ethyl-5-methyl-8-((R)-tetrahydrofuran-3-yl)-7,8-dihydropteridin-6(5H)-one
• 英文别名: (7R)-2-chloro-7-ethyl-5-methyl-8-[(3R)-oxolan-3-yl]-7H-pteridin-6-one
• 化学式: C₁₃H₁₇ClN₄O₂
• 分子量: 296.757
• InChiKey: OKEMFFYKCCKRHM-RKDXNWHRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  20
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  58.6
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-苯基咪唑 、 (R)-2-chloro-7-ethyl-5-methyl-8-((R)-tetrahydrofuran-3-yl)-7,8-dihydropteridin-6(5H)-one 在 tris-(dibenzylideneacetone)dipalladium(0) 、 caesium carbonate 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 作用下， 反应 1.0h， 生成 (R)-7-ethyl-5-methyl-2-(2-phenyl-1H-imidazol-1-yl)-8-((R)-tetrahydrofuran-3-yl)-7,8-dihydropteridin-6(5H)-one
  参考文献：
  名称：

  Design and synthesis of highly selective, orally active Polo-like kinase-2 (Plk-2) inhibitors

  摘要：

  Polo-like kinase-2 (Plk-2) is a potential therapeutic target for Parkinson's disease and this Letter describes the SAR of a series of dihydropteridinone based Plk-2 inhibitors. By optimizing both the N-8 substituent and the biaryl region of the inhibitors we obtained single digit nanomolar compounds such as 37 with excellent selectivity for Plk-2 over Plk-1. When dosed orally in rats, compound 37 demonstrated a 41-45% reduction of pS129-alpha-synuclein levels in the cerebral cortex. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.02.065
• 作为产物：
  描述：

  磷酸三甲酯 、 (7R)-2-chloro-7-ethyl-8-[(3R)-oxolan-3-yl]-5,7-dihydropteridin-6-one 在 potassium carbonate 作用下， 以 1,4-二氧六环 为溶剂， 反应 18.0h， 生成 (R)-2-chloro-7-ethyl-5-methyl-8-((R)-tetrahydrofuran-3-yl)-7,8-dihydropteridin-6(5H)-one
  参考文献：
  名称：

  Design and synthesis of highly selective, orally active Polo-like kinase-2 (Plk-2) inhibitors

  摘要：

  Polo-like kinase-2 (Plk-2) is a potential therapeutic target for Parkinson's disease and this Letter describes the SAR of a series of dihydropteridinone based Plk-2 inhibitors. By optimizing both the N-8 substituent and the biaryl region of the inhibitors we obtained single digit nanomolar compounds such as 37 with excellent selectivity for Plk-2 over Plk-1. When dosed orally in rats, compound 37 demonstrated a 41-45% reduction of pS129-alpha-synuclein levels in the cerebral cortex. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.02.065

文献信息

• Selective and Brain-Permeable Polo-like Kinase-2 (Plk-2) Inhibitors That Reduce α-Synuclein Phosphorylation in Rat Brain
  作者：Danielle L. Aubele、Roy K. Hom、Marc Adler、Robert A. Galemmo、Simeon Bowers、Anh P. Truong、Hu Pan、Paul Beroza、R. Jeffrey Neitz、Nanhua Yao、May Lin、George Tonn、Heather Zhang、Michael P. Bova、Zhao Ren、Danny Tam、Lany Ruslim、Jeanne Baker、Linnea Diep、Kent Fitzgerald、Jennifer Hoffman、Ruth Motter、Donald Fauss、Pearl Tanaka、Michael Dappen、Jacek Jagodzinski、Wayman Chan、Andrei W. Konradi、Lee Latimer、Yong L. Zhu、Hing L. Sham、John P. Anderson、Marcelle Bergeron、Dean R. Artis

  DOI：10.1002/cmdc.201300166

  日期：2013.8

  involved in the phosphorylation of α‐synuclein in Lewy bodies, which are one of the hallmarks of Parkinson’s disease neuropathology. Potent, selective, brain‐penetrant inhibitors of Plk‐2 were obtained from a structure‐guided drug discovery approach driven by the first reported Plk‐2–inhibitor complexes. The best of these compounds showed excellent isoform and kinome‐wide selectivity, with physicochemical

  Polo-like kinase-2（Plk-2）被认为是路易体中α-突触核蛋白磷酸化的主要激酶，这是帕金森氏病神经病理学的标志之一。有效的，选择性的，脑渗透性的Plk-2抑制剂是从第一个报道的Plk-2抑制剂复合物驱动的结构指导药物发现方法获得的。这些化合物中最好的化合物表现出出色的同工型和全基因组选择性，其理化特性足以证实体内Plk-2抑制作用。一种这样的化合物在口服后可显着降低大鼠脑内α-突触核蛋白的磷酸化，并为该治疗途径对帕金森氏病的潜在治疗的未来研究提供了有用的探针。
• Design and synthesis of highly selective, orally active Polo-like kinase-2 (Plk-2) inhibitors
  作者：Simeon Bowers、Anh P. Truong、Michael Ye、Danielle L. Aubele、Jennifer M. Sealy、R. Jeffrey Neitz、Roy K. Hom、Wayman Chan、Michael S. Dappen、Robert A. Galemmo、Andrei W. Konradi、Hing L. Sham、Yong L. Zhu、Paul Beroza、George Tonn、Heather Zhang、Jennifer Hoffman、Ruth Motter、Donald Fauss、Pearl Tanaka、Michael P. Bova、Zhao Ren、Danny Tam、Lany Ruslim、Jeanne Baker、Deepal Pandya、Linnea Diep、Kent Fitzgerald、Dean R. Artis、John P. Anderson、Marcelle Bergeron

  DOI：10.1016/j.bmcl.2013.02.065

  日期：2013.5

  Polo-like kinase-2 (Plk-2) is a potential therapeutic target for Parkinson's disease and this Letter describes the SAR of a series of dihydropteridinone based Plk-2 inhibitors. By optimizing both the N-8 substituent and the biaryl region of the inhibitors we obtained single digit nanomolar compounds such as 37 with excellent selectivity for Plk-2 over Plk-1. When dosed orally in rats, compound 37 demonstrated a 41-45% reduction of pS129-alpha-synuclein levels in the cerebral cortex. (C) 2013 Elsevier Ltd. All rights reserved.