N1-(4-(4-(4-fluorophenyl)-2-(methylthio)-1H-imidazol-5-yl)pyridin-2-yl)benzene-1,4-diamine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: N1-(4-(4-(4-fluorophenyl)-2-(methylthio)-1H-imidazol-5-yl)pyridin-2-yl)benzene-1,4-diamine
• 英文别名: N-(4-(4-(4-fluorophenyl)-2-(methylthio)-1H-imidazol-5-yl)pyridin-2-yl)benzene-1,4-diamine；4-N-[4-[5-(4-fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl]pyridin-2-yl]benzene-1,4-diamine
• 化学式: C₂₁H₁₈FN₅S
• 分子量: 391.472
• InChiKey: ZTEDFSIIEDNHLZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  105
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  N1-(4-(4-(4-fluorophenyl)-2-(methylthio)-1H-imidazol-5-yl)pyridin-2-yl)benzene-1,4-diamine 在 tin(II) chloride dihdyrate 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 14.0h， 生成 3-acrylamido-N-(4-((4-(4-(4-fluorophenyl)-2-(methylthio)-1H-imidazol-5-yl)pyridin-2-yl)amino)phenyl)benzamide
  参考文献：
  名称：

  Tri- and Tetrasubstituted Pyridinylimidazoles as Covalent Inhibitors of c-Jun N-Terminal Kinase 3

  摘要：

  The concept of covalent inhibition of c-Jun N-terminal kinase 3 (JNK3) was successfully transferred to our well validated pyridinylimidazole scaffold varying several structural features in order to deduce crucial structure-activity relationships. Joint targeting of the hydrophobic region I and methylation of imidazole-N1 position increased the activity and reduced the number of off-targets. The most promising covalent inhibitor, the tetrasubstituted imidazole 3-acrylamido-N-(4-((4-(4-(4-fluoropheny1)-1-methyl-2-(methylthio)-1H-imidazol-S-yl)pyridin-2-yl)amino)phenyl)benzamide (7) inhibits the JNK3 in the subnanomolar range (IC50 = 0.3 nM), shows high metabolic stability in human liver microsomes, and displays excellent selectivity in a screening against a panel of 410 kinases. Covalent bond formation to Cys-154 was confirmed by incubation of the inhibitors with wild-type JNK3 and JNK3-C154A mutant followed by mass spectrometry.

  DOI：

  10.1021/acs.jmedchem.6b01180
• 作为产物：
  描述：

  对苯二胺 、 2-chloro-4-(4-(4-fluorophenyl)-2-(methylthio)-1H-imidazol-5-yl)pyridine 在 盐酸 作用下， 以 乙醇 、 正丁醇 为溶剂， 反应 16.0h， 以88%的产率得到N1-(4-(4-(4-fluorophenyl)-2-(methylthio)-1H-imidazol-5-yl)pyridin-2-yl)benzene-1,4-diamine
  参考文献：
  名称：

  基于荧光偏振的检测方法，用于检测与非活性c-Jun N末端激酶3和p38α丝裂原活化的蛋白激酶结合的化合物

  摘要：

  合成了两种荧光素标记的吡啶基咪唑并用作探针，用于测定潜在的激酶抑制剂与c-Jun N端激酶3（JNK3）和p38α促丝裂原激活的蛋白激酶（MAPK）的结合亲和力。使用1-（3'，6'-dihydroxy-3-oxo-3H-spiro [isobenzofuran-1,9'-xanthen] -5-yl）-开发了两种酶的基于荧光偏振（FP）的竞争结合测定法3-（4-（（4-（4-（4-氟苯基）-2-（甲硫基）-1H-咪唑-5-基）吡啶-2--2-基）氨基）苯基）硫脲（5）作为FP探针（JNK3：Kd ＝ 3.0nM；p38αMAPK：Kd ＝ 5.7nM）。用已知的JNK3和p38αMAPK抑制剂进行测定的验证表明，两种FP测定均与活性测定收到的抑制数据非常相关。这，

  DOI：

  10.1016/j.ab.2016.02.018

文献信息

• Fluorescence polarization-based assays for detecting compounds binding to inactive c-Jun N-terminal kinase 3 and p38α mitogen-activated protein kinase
  作者：Francesco Ansideri、Andreas Lange、Ahmed El-Gokha、Frank M. Boeckler、Pierre Koch

  DOI：10.1016/j.ab.2016.02.018

  日期：2016.6

  Two fluorescein-labeled pyridinylimidazoles were synthesized and evaluated as probes for the binding affinity determination of potential kinase inhibitors to the c-Jun N-terminal kinase 3 (JNK3) and p38α mitogen-activated protein kinase (MAPK). Fluorescence polarization (FP)-based competition binding assays were developed for both enzymes using 1-(3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-

  合成了两种荧光素标记的吡啶基咪唑并用作探针，用于测定潜在的激酶抑制剂与c-Jun N端激酶3（JNK3）和p38α促丝裂原激活的蛋白激酶（MAPK）的结合亲和力。使用1-（3'，6'-dihydroxy-3-oxo-3H-spiro [isobenzofuran-1,9'-xanthen] -5-yl）-开发了两种酶的基于荧光偏振（FP）的竞争结合测定法3-（4-（（4-（4-（4-氟苯基）-2-（甲硫基）-1H-咪唑-5-基）吡啶-2--2-基）氨基）苯基）硫脲（5）作为FP探针（JNK3：Kd ＝ 3.0nM；p38αMAPK：Kd ＝ 5.7nM）。用已知的JNK3和p38αMAPK抑制剂进行测定的验证表明，两种FP测定均与活性测定收到的抑制数据非常相关。这，
• Tri- and Tetrasubstituted Pyridinylimidazoles as Covalent Inhibitors of c-Jun N-Terminal Kinase 3
  作者：Felix Muth、Ahmed El-Gokha、Francesco Ansideri、Michael Eitel、Eva Döring、Adrian Sievers-Engler、Andreas Lange、Frank M. Boeckler、Michael Lämmerhofer、Pierre Koch、Stefan A. Laufer

  DOI：10.1021/acs.jmedchem.6b01180

  日期：2017.1.26

  The concept of covalent inhibition of c-Jun N-terminal kinase 3 (JNK3) was successfully transferred to our well validated pyridinylimidazole scaffold varying several structural features in order to deduce crucial structure-activity relationships. Joint targeting of the hydrophobic region I and methylation of imidazole-N1 position increased the activity and reduced the number of off-targets. The most promising covalent inhibitor, the tetrasubstituted imidazole 3-acrylamido-N-(4-((4-(4-(4-fluoropheny1)-1-methyl-2-(methylthio)-1H-imidazol-S-yl)pyridin-2-yl)amino)phenyl)benzamide (7) inhibits the JNK3 in the subnanomolar range (IC50 = 0.3 nM), shows high metabolic stability in human liver microsomes, and displays excellent selectivity in a screening against a panel of 410 kinases. Covalent bond formation to Cys-154 was confirmed by incubation of the inhibitors with wild-type JNK3 and JNK3-C154A mutant followed by mass spectrometry.