Ethyl 5-ethyl-4-{[5-(methoxycarbamoyl)-2-methylphenyl]amino}pyrrolo[1,2-a][1,2,4]triazine-6-carboxylate | 1005196-69-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: Ethyl 5-ethyl-4-{[5-(methoxycarbamoyl)-2-methylphenyl]amino}pyrrolo[1,2-a][1,2,4]triazine-6-carboxylate
• 英文别名: ethyl 5-ethyl-4-[5-(methoxycarbamoyl)-2-methylanilino]pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate
• CAS: 1005196-69-9
• 化学式: C₂₀H₂₃N₅O₄
• 分子量: 397.434
• InChiKey: BNIIGLKXXNSSKW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  29
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  107
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  4-氯-5-乙基-吡咯并[2,1-f][1,2,4]三嗪-6-羧酸乙酯 、 N-methoxy-3-amino-4-methylbenzamide hydrochloride 以 N,N-二甲基甲酰胺 为溶剂， 生成 Ethyl 5-ethyl-4-{[5-(methoxycarbamoyl)-2-methylphenyl]amino}pyrrolo[1,2-a][1,2,4]triazine-6-carboxylate
  参考文献：
  名称：

  Design, Synthesis, and Anti-inflammatory Properties of Orally Active 4-(Phenylamino)-pyrrolo[2,1-f][1,2,4]triazine p38α Mitogen-Activated Protein Kinase Inhibitors

  摘要：

  A novel structural class of p38 mitogen-activated protein (MAP) kinase inhibitors consisting of substituted 4-(phenylamino)-pyrrolo[2,1- f][1,2,4]triazines has been discovered. An initial subdeck screen revealed that the oxindole-pyrrolo[2,1- f][1,2,4]triazine lead 2a displayed potent enzyme inhibition (IC 50 60 nM) and was active in a cell-based TNFalpha biosynthesis inhibition assay (IC 50 210 nM). Replacement of the C4 oxindole with 2-methyl-5- N-methoxybenzamide aniline 9 gave a compound with superior p38 kinase inhibition (IC 50 10 nM) and moderately improved functional inhibition in THP-1 cells. Further replacement of the C6 ester of the pyrrolo[2,1- f][1,2,4]triazine with amides afforded compounds with increased potency, excellent oral bioavailability, and robust efficacy in a murine model of acute inflammation (murine LPS-TNFalpha). In rodent disease models of chronic inflammation, multiple compounds demonstrated significant inhibition of disease progression leading to the advancement of 2 compounds 11b and 11j into further preclinical and toxicological studies.

  DOI：

  10.1021/jm7009414

文献信息

• Design, Synthesis, and Anti-inflammatory Properties of Orally Active 4-(Phenylamino)-pyrrolo[2,1-<i>f</i>][1,2,4]triazine p38α Mitogen-Activated Protein Kinase Inhibitors
  作者：John Hynes、Alaric J. Dyckman、Shuqun Lin、Stephen T. Wrobleski、Hong Wu、Kathleen M. Gillooly、Steven B. Kanner、Herinder Lonial、Derek Loo、Kim W. McIntyre、Sidney Pitt、Ding Ren Shen、David J. Shuster、XiaoXia Yang、Rosemary Zhang、Kamelia Behnia、Hongjian Zhang、Punit H. Marathe、Arthur M. Doweyko、John S. Tokarski、John S. Sack、Matthew Pokross、Susan E. Kiefer、John A. Newitt、Joel C. Barrish、John Dodd、Gary L. Schieven、Katerina Leftheris

  DOI：10.1021/jm7009414

  日期：2008.1.1

  A novel structural class of p38 mitogen-activated protein (MAP) kinase inhibitors consisting of substituted 4-(phenylamino)-pyrrolo[2,1- f][1,2,4]triazines has been discovered. An initial subdeck screen revealed that the oxindole-pyrrolo[2,1- f][1,2,4]triazine lead 2a displayed potent enzyme inhibition (IC 50 60 nM) and was active in a cell-based TNFalpha biosynthesis inhibition assay (IC 50 210 nM). Replacement of the C4 oxindole with 2-methyl-5- N-methoxybenzamide aniline 9 gave a compound with superior p38 kinase inhibition (IC 50 10 nM) and moderately improved functional inhibition in THP-1 cells. Further replacement of the C6 ester of the pyrrolo[2,1- f][1,2,4]triazine with amides afforded compounds with increased potency, excellent oral bioavailability, and robust efficacy in a murine model of acute inflammation (murine LPS-TNFalpha). In rodent disease models of chronic inflammation, multiple compounds demonstrated significant inhibition of disease progression leading to the advancement of 2 compounds 11b and 11j into further preclinical and toxicological studies.