N-{4-[3-(2,2-dimethoxyethyl)-5-(4-fluorophenyl)-1-oxy-3H-imidazol-4-yl]pyridin-2-yl}acetamide | 820241-26-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: N-{4-[3-(2,2-dimethoxyethyl)-5-(4-fluorophenyl)-1-oxy-3H-imidazol-4-yl]pyridin-2-yl}acetamide
• 英文别名: N-[4-[3-(2,2-dimethoxyethyl)-5-(4-fluorophenyl)-1-oxidoimidazol-1-ium-4-yl]pyridin-2-yl]acetamide
• CAS: 820241-26-7
• 化学式: C₂₀H₂₁FN₄O₄
• 分子量: 400.41
• InChiKey: CUVZHPWOQJUIDC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  29
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  90.8
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  N-{4-[3-(2,2-dimethoxyethyl)-5-(4-fluorophenyl)-1-oxy-3H-imidazol-4-yl]pyridin-2-yl}acetamide 在 2,2,4,4-四甲基-1,3-环丁烷二硫酮 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 以81%的产率得到N-(4-(3-(2,2-dimethoxyethyl)-5-(4-fluorophenyl)-2-thioxo-2,3-dihydro-1H-imidazol-4-yl)pyridin-2-yl)acetamide
  参考文献：
  名称：

  四取代的吡啶并咪唑类化合物作为p38α丝裂原活化蛋白激酶和c-Jun N端激酶3的双重抑制剂，可潜在治疗神经退行性疾病

  摘要：

  四取代的咪唑被设计为c-Jun N末端激酶（JNK）3和p38α丝裂原活化蛋白（MAP）激酶的双重抑制剂。制备了45种衍生物的文库，并在激酶活性分析中评估了它们抑制JNK3和p38αMAP激酶这两种激酶的能力。两种酶的IC 50值均降至低两位数纳摩尔范围的双重抑制剂已被鉴定。最佳平衡的双重JNK3 /p38αMAP激酶抑制剂为6m（IC 50：JNK3，18 nM;p38α，30 nM）和14d（IC 50：JNK3，26 nM；p38α，34 nM）兼具出色的溶解性和代谢稳定性。它们可以用作临床前原则证明研究的有用工具化合物，以验证两种激酶在亨廷顿舞蹈病进展中的协同作用。

  DOI：

  10.1021/jm501557a
• 作为产物：
  描述：

  2-乙酰基氨基异烟酸 在 4-二甲氨基吡啶 、 氢溴酸 、 sodium methylate 、 N,N'-羰基二咪唑 、 亚硝酸异戊酯 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 为溶剂， 反应 47.75h， 生成 N-{4-[3-(2,2-dimethoxyethyl)-5-(4-fluorophenyl)-1-oxy-3H-imidazol-4-yl]pyridin-2-yl}acetamide
  参考文献：
  名称：

  Tetrasubstituted Imidazole Inhibitors of Cytokine Release:  Probing Substituents in the N-1 Position

  摘要：

  We prepared novel 1,2,4,5-tetrasubstituted imidazole derivatives with high anti-inflammatory activity by using our previously described regiospecific synthesis. Systematic optimization of the imidazole N-1 substituent resulted in compound 9b that potently inhibited the mitogen-activated protein kinase p38 (p38 IC50 = 0.218 muM) as well as the release of the proinflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor alpha. (TNFalpha) from human whole blood after stimulation with LPS. Furthermore, compound 9b exhibited reduced cytochrome P450 interaction in comparison with SB203580. This result is particularly important, since cytochrome P450 interaction is observed for some p38 inhibitors and in turn can potentially cause drug-drug interaction or lead to other hepatic changes such as P450 enzyme induction.

  DOI：

  10.1021/jm0496584

文献信息

• <i>Tetra</i>-Substituted Pyridinylimidazoles As Dual Inhibitors of p38α Mitogen-Activated Protein Kinase and c-Jun <i>N</i>-Terminal Kinase 3 for Potential Treatment of Neurodegenerative Diseases
  作者：Felix Muth、Marcel Günther、Silke M. Bauer、Eva Döring、Sabine Fischer、Julia Maier、Peter Drückes、Jürgen Köppler、Jörg Trappe、Ulrich Rothbauer、Pierre Koch、Stefan A. Laufer

  DOI：10.1021/jm501557a

  日期：2015.1.8

  Tetra-substituted imidazoles were designed as dual inhibitors of c-Jun N-terminal kinase (JNK) 3 and p38α mitogen-activated protein (MAP) kinase. A library of 45 derivatives was prepared and evaluated in a kinase activity assay for their ability to inhibit both kinases, JNK3 and p38α MAP kinase. Dual inhibitors with IC50 values down to the low double-digit nanomolar range at both enzymes were identified

  四取代的咪唑被设计为c-Jun N末端激酶（JNK）3和p38α丝裂原活化蛋白（MAP）激酶的双重抑制剂。制备了45种衍生物的文库，并在激酶活性分析中评估了它们抑制JNK3和p38αMAP激酶这两种激酶的能力。两种酶的IC 50值均降至低两位数纳摩尔范围的双重抑制剂已被鉴定。最佳平衡的双重JNK3 /p38αMAP激酶抑制剂为6m（IC 50：JNK3，18 nM;p38α，30 nM）和14d（IC 50：JNK3，26 nM；p38α，34 nM）兼具出色的溶解性和代谢稳定性。它们可以用作临床前原则证明研究的有用工具化合物，以验证两种激酶在亨廷顿舞蹈病进展中的协同作用。
• Tetrasubstituted Imidazole Inhibitors of Cytokine Release:  Probing Substituents in the N-1 Position
  作者：Stefan A. Laufer、Werner Zimmermann、Kathrin J. Ruff

  DOI：10.1021/jm0496584

  日期：2004.12.1

  We prepared novel 1,2,4,5-tetrasubstituted imidazole derivatives with high anti-inflammatory activity by using our previously described regiospecific synthesis. Systematic optimization of the imidazole N-1 substituent resulted in compound 9b that potently inhibited the mitogen-activated protein kinase p38 (p38 IC50 = 0.218 muM) as well as the release of the proinflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor alpha. (TNFalpha) from human whole blood after stimulation with LPS. Furthermore, compound 9b exhibited reduced cytochrome P450 interaction in comparison with SB203580. This result is particularly important, since cytochrome P450 interaction is observed for some p38 inhibitors and in turn can potentially cause drug-drug interaction or lead to other hepatic changes such as P450 enzyme induction.