6-(2,4-difluorophenoxy)-8-methyl-2-(piperidin-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one | 1280218-56-5

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 6-(2,4-difluorophenoxy)-8-methyl-2-(piperidin-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one
• 英文别名: 6-(2,4-Difluorophenoxy)-8-methyl-2-(piperidin-4-ylamino)pyrido[2,3-d]pyrimidin-7-one；6-(2,4-difluorophenoxy)-8-methyl-2-(piperidin-4-ylamino)pyrido[2,3-d]pyrimidin-7-one
• CAS: 1280218-56-5
• 化学式: C₁₉H₁₉F₂N₅O₂
• 分子量: 387.389
• InChiKey: GNRWBVNBKBFCAQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  79.4
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  6-(2,4-difluorophenoxy)-8-methyl-2-(piperidin-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one 在 盐酸 、 二乙基异丙基胺 作用下， 以 四氢呋喃 、 乙醚 为溶剂， 反应 0.5h， 生成 2-(1-acetylpiperidin-4-ylamino)-6-(2,4-difluorophenoxy)-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride
  参考文献：
  名称：

  Discovery of 6-(2,4-Difluorophenoxy)-2-[3-hydroxy-1-(2-hydroxyethyl)propylamino]-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (Pamapimod) and 6-(2,4-Difluorophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (R1487) as Orally Bioavailable and Highly Selective Inhibitors of p38α Mitogen-Activated Protein Kinase

  摘要：

  The development of a new series of p38 alpha inhibitors resulted in the identification of two clinical candidates, one of which was advanced into a phase 2 clinical study for rheumatoid arthritis. The original lead, an lck inhibitor that also potently inhibited p38a, was a screening hit from our kinase inhibitor library. This manuscript describes the optimization of the lead to p38-selective examples with good pharmacokinetic properties.

  DOI：

  10.1021/jm101423y
• 作为产物：
  描述：

  4-甲胺基-2-甲硫基-5-嘧啶甲酸乙酯 在 manganese(IV) oxide 、 lithium aluminium tetrahydride 、 甲酸 、 双氧水 、 sodium carbonate 、 potassium carbonate 、 氯甲酸氯乙酯 作用下， 以 四氢呋喃 、 N-甲基吡咯烷酮 、 甲醇 、 二氯甲烷 、 水 、 1,2-二氯乙烷 为溶剂， 反应 210.25h， 生成 6-(2,4-difluorophenoxy)-8-methyl-2-(piperidin-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one
  参考文献：
  名称：

  Discovery of 6-(2,4-Difluorophenoxy)-2-[3-hydroxy-1-(2-hydroxyethyl)propylamino]-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (Pamapimod) and 6-(2,4-Difluorophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (R1487) as Orally Bioavailable and Highly Selective Inhibitors of p38α Mitogen-Activated Protein Kinase

  摘要：

  The development of a new series of p38 alpha inhibitors resulted in the identification of two clinical candidates, one of which was advanced into a phase 2 clinical study for rheumatoid arthritis. The original lead, an lck inhibitor that also potently inhibited p38a, was a screening hit from our kinase inhibitor library. This manuscript describes the optimization of the lead to p38-selective examples with good pharmacokinetic properties.

  DOI：

  10.1021/jm101423y

文献信息

• Novel compounds reducing IRS-1 serine phosphorylation for treatment of diabetes
  作者：Laura Simon-Szabó、Márton Kokas、Zoltán Greff、Sándor Boros、Péter Bánhegyi、Lilián Zsákai、Csaba Szántai-Kis、Tibor Vantus、József Mandl、Gábor Bánhegyi、István Vályi-Nagy、László Őrfi、Axel Ullrich、Miklós Csala、György Kéri

  DOI：10.1016/j.bmcl.2015.11.099

  日期：2016.1

  substrate 1 (IRS-1) at serine 307 play a central role both in insulin resistance and in β-cell dysfunction. IRS-1 phosphorylation is stimulated by elevated free fatty acid levels through different pathways in obesity. A series of novel pyrido[2,3-d]pyrimidin-7-one derivatives were synthesized as potential antidiabetic agents, preventing IRS-1 phosphorylation at serine 307 in a cellular model of lipotoxicity

  各种相互作用的应激激酶，特别是c-Jun N末端激酶（JNK）的激活，以及伴随着丝氨酸307的胰岛素受体底物1（IRS-1）的磷酸化，在胰岛素抵抗和β细胞中均起着中心作用功能障碍。通过肥胖中不同途径的升高的游离脂肪酸水平可刺激IRS-1磷酸化。合成了一系列新型的吡啶并[2,3 - d ]嘧啶-7-衍生物，作为潜在的抗糖尿病药，可防止脂毒性和2型糖尿病细胞模型中IRS-1在丝氨酸307的磷酸化。