1-[2-(4-Aminophenyl)-5-tert-butyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]urea | 611168-78-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 1-[2-(4-Aminophenyl)-5-tert-butyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]urea
• 英文别名: 1-[2-(4-aminophenyl)-5-tert-butylpyrazol-3-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea
• CAS: 611168-78-6
• 化学式: C₃₀H₃₆N₆O₃
• 分子量: 528.654
• InChiKey: FNOHHJHSNNPXEW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  39
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  107
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  乙酰氯 、 1-[2-(4-Aminophenyl)-5-tert-butyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]urea 在 吡啶 作用下， 以 四氢呋喃 为溶剂， 生成 N-(4-{3-tert-butyl-5-[({4-[2-(morpholin-4-yl)ethoxy]naphthalen-1-yl}carbamoyl)amino]-1H-pyrazol-1-yl}phenyl)acetamide
  参考文献：
  名称：

  Structure−Activity Relationships of the p38α MAP Kinase Inhibitor 1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naph- thalen-1-yl]urea (BIRB 796)

  摘要：

  We report on the structure-activity relationships (SAR) of 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]urea (BIRB 796), an inhibitor of p38alpha MAP kinase which has advanced into human clinical trials for the treatment of autoimmune diseases. Thermal denaturation was used to establish molecular binding affinities for this class of p38alpha inhibitors. The tert-butyl group remains a critical binding element by occupying a lipophilic domain in the kinase which is exposed upon rearrangement of the activation loop. An aromatic ring attached to N-2 of the pyrazole nucleus provides important pi-CH2 interactions with the kinase. The role of groups attached through an ethoxy group to the 4-position of the naphthalene and directed into the ATP-binding domain is elucidated. Pharmacophores with good hydrogen bonding potential, such as morpholine, pyridine, and imidazole, shift the melting temperature of p38alpha by 16-17 degreesC translating into K-d values of 50-100 pM. Finally, we describe several compounds that potently inhibit TNF-alpha production when dosed orally in mice.

  DOI：

  10.1021/jm030121k
• 作为产物：
  描述：

  3-叔丁基-1-(4-硝基苯基)-1H-吡唑-5-胺 在 palladium on activated charcoal 吡啶 、 ammonium formate 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 乙醇 、 二甲基亚砜 为溶剂， 生成 1-[2-(4-Aminophenyl)-5-tert-butyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]urea
  参考文献：
  名称：

  Structure−Activity Relationships of the p38α MAP Kinase Inhibitor 1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naph- thalen-1-yl]urea (BIRB 796)

  摘要：

  We report on the structure-activity relationships (SAR) of 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]urea (BIRB 796), an inhibitor of p38alpha MAP kinase which has advanced into human clinical trials for the treatment of autoimmune diseases. Thermal denaturation was used to establish molecular binding affinities for this class of p38alpha inhibitors. The tert-butyl group remains a critical binding element by occupying a lipophilic domain in the kinase which is exposed upon rearrangement of the activation loop. An aromatic ring attached to N-2 of the pyrazole nucleus provides important pi-CH2 interactions with the kinase. The role of groups attached through an ethoxy group to the 4-position of the naphthalene and directed into the ATP-binding domain is elucidated. Pharmacophores with good hydrogen bonding potential, such as morpholine, pyridine, and imidazole, shift the melting temperature of p38alpha by 16-17 degreesC translating into K-d values of 50-100 pM. Finally, we describe several compounds that potently inhibit TNF-alpha production when dosed orally in mice.

  DOI：

  10.1021/jm030121k