4-[3-[4-(7-ethyl-8-oxo-8,9-dihydro-7H-purin-6-yl)phenyl]-ureido]-N-isopropylbenzamide | 1219727-40-8

• 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: 4-[3-[4-(7-ethyl-8-oxo-8,9-dihydro-7H-purin-6-yl)phenyl]-ureido]-N-isopropylbenzamide
• 英文别名: 3-(3-(4-(7-ethyl-8-oxo-8,9-dihydro-7H-purin-6-yl)phenyl)ureido)-N-isopropylbenzamide；3-[[4-(7-ethyl-8-oxo-9H-purin-6-yl)phenyl]carbamoylamino]-N-propan-2-ylbenzamide
• CAS: 1219727-40-8
• 化学式: C₂₄H₂₅N₇O₃
• 分子量: 459.508
• InChiKey: IVWHDODYYCRXLZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  34
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  128
• 氢给体数：
  4
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  间氨基苯甲酸 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 四(三苯基膦)钯 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.0h， 生成 4-[3-[4-(7-ethyl-8-oxo-8,9-dihydro-7H-purin-6-yl)phenyl]-ureido]-N-isopropylbenzamide
  参考文献：
  名称：

  Bis-aryl Urea Derivatives as Potent and Selective LIM Kinase (Limk) Inhibitors

  摘要：

  The discovery/optimization of bis-aryl ureas as Limk inhibitors to obtain high potency and selectivity and appropriate pharmacokinetic properties through systematic SAR studies is reported. Docking studies supported the observed SAR. Optimized Limk inhibitors had high biochemical potency (IC50 < 25 nM), excellent selectivity against ROCK and JNK kinases (>400-fold), potent inhibition of cofilin phosphorylation in A7r5, PC-3, and CEM-SS T cells (IC50 < 1 mu M), and good in vitro and in vivo pharmacokinetic properties. In the profiling against a panel of 61 kinases, compound 18b at 1 mu M inhibited only Limk1 and STK16 with >= 80% inhibition. Compounds 18b and 18f were highly efficient in inhibiting cell-invasion/migration in PC-3 cells. In addition, compound 18w was demonstrated to be effective on reducing intraocular pressure (IOP) on rat eyes. Taken together, these data demonstrated that we had developed a novel class of bis-aryl urea derived potent and selective Limk inhibitors.

  DOI：

  10.1021/jm501680m

文献信息

• [EN] UREA AND CARBAMATE COMPOUNDS AND ANALOGS AS KINASE INHIBITORS<br/>[FR] COMPOSÉS D'URÉE ET DE CARBAMATE ET ANALOGUES UTILISÉS COMME INHIBITEURS DE KINASE
  申请人：FENG YANGBO

  公开号：WO2010036316A1

  公开（公告）日：2010-04-01

  The invention is directed to compounds that can inhibit the bioactivity of one or more kinases such as any of Rho kinases, PKB (Akt) kinases, p70S6K kinase, LIM kinases, or IKK kinases, to methods of use of those compounds, and to methods of preparation of those compounds The inventive compounds can be used In the treatment of a variety of medical malconditions.

  该发明涉及可以抑制一个或多个激酶的生物活性的化合物，如Rho激酶、PKB（Akt）激酶、p70S6K激酶、LIM激酶或IKK激酶中的任何一个，以及这些化合物的使用方法和制备方法。这些创新的化合物可用于治疗各种医疗疾病。
• Bis-aryl Urea Derivatives as Potent and Selective LIM Kinase (Limk) Inhibitors
  作者：Yan Yin、Ke Zheng、Nibal Eid、Shannon Howard、Ji-Hak Jeong、Fei Yi、Jia Guo、Chul Min Park、Mathieu Bibian、Weilin Wu、Pamela Hernandez、HaJeung Park、Yuntao Wu、Jun-Li Luo、Philip V. LoGrasso、Yangbo Feng

  DOI：10.1021/jm501680m

  日期：2015.2.26

  The discovery/optimization of bis-aryl ureas as Limk inhibitors to obtain high potency and selectivity and appropriate pharmacokinetic properties through systematic SAR studies is reported. Docking studies supported the observed SAR. Optimized Limk inhibitors had high biochemical potency (IC50 < 25 nM), excellent selectivity against ROCK and JNK kinases (>400-fold), potent inhibition of cofilin phosphorylation in A7r5, PC-3, and CEM-SS T cells (IC50 < 1 mu M), and good in vitro and in vivo pharmacokinetic properties. In the profiling against a panel of 61 kinases, compound 18b at 1 mu M inhibited only Limk1 and STK16 with >= 80% inhibition. Compounds 18b and 18f were highly efficient in inhibiting cell-invasion/migration in PC-3 cells. In addition, compound 18w was demonstrated to be effective on reducing intraocular pressure (IOP) on rat eyes. Taken together, these data demonstrated that we had developed a novel class of bis-aryl urea derived potent and selective Limk inhibitors.