1-methyl-5-{5-nitro-2-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-1H-pyrazole | 1227254-34-3

• 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-methyl-5-{5-nitro-2-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-1H-pyrazole
• 英文别名: 1-Methyl-5-[5-nitro-2-(2-pyrrolidin-1-ylethoxy)phenyl]pyrazole
• CAS: 1227254-34-3
• 化学式: C₁₆H₂₀N₄O₃
• 分子量: 316.36
• InChiKey: YRHKYGCFZPCNCO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  23
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  76.1
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-methyl-5-{5-nitro-2-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-1H-pyrazole 在 氯化铵 、 锌 作用下， 以 四氢呋喃 、 水 为溶剂， 生成 3-(1-methyl-1H-pyrazol-5-yl)-4-[2-(pyrrolidin-1-yl)ethoxy]aniline
  参考文献：
  名称：

  Discovery and Structure−Activity Relationship of 3-Methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide (APD791): A Highly Selective 5-Hydroxytryptamine_2A Receptor Inverse Agonist for the Treatment of Arterial Thrombosis

  摘要：

  Serotonin, which is stored in platelets and is released during thrombosis, activates platelets via the 5-HT2A receptor. 5-HT2A receptor inverse agonists thus represent a potential new class of antithrombotic agents. Our medicinal program began with known compounds that displayed binding affinity for the recombinant 5-HT2A receptor, but which had poor activity when tested in human plasma platelet inhibition assays. We herein describe a series of phenyl pyrazole inverse agonists optimized for selectivity, aqueous solubility, antiplatelet activity, low hERG activity, and good pharmacokinetic properties, resulting in the discovery of 10k (APD791). 10k inhibited serotonin-amplified human platelet aggregation with an IC50 = 8.7 nM and had negligible binding affinity for the closely related 5-HT2B and 5-HT2C receptors. 10k was orally bioavailable in rats, dogs, and monkeys and had an acceptable safety profile. As a result, 10k was selected further evaluation and advanced into clinical development as a potential treatment for arterial thrombosis.

  DOI：

  10.1021/jm100044a
• 作为产物：
  描述：

  四氢吡咯 、 5-[2-(2-bromo-ethoxy)-5-nitro-phenyl]-1-methyl-1H-pyrazole 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.25h， 生成 1-methyl-5-{5-nitro-2-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-1H-pyrazole
  参考文献：
  名称：

  Discovery and Structure−Activity Relationship of 3-Methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide (APD791): A Highly Selective 5-Hydroxytryptamine_2A Receptor Inverse Agonist for the Treatment of Arterial Thrombosis

  摘要：

  Serotonin, which is stored in platelets and is released during thrombosis, activates platelets via the 5-HT2A receptor. 5-HT2A receptor inverse agonists thus represent a potential new class of antithrombotic agents. Our medicinal program began with known compounds that displayed binding affinity for the recombinant 5-HT2A receptor, but which had poor activity when tested in human plasma platelet inhibition assays. We herein describe a series of phenyl pyrazole inverse agonists optimized for selectivity, aqueous solubility, antiplatelet activity, low hERG activity, and good pharmacokinetic properties, resulting in the discovery of 10k (APD791). 10k inhibited serotonin-amplified human platelet aggregation with an IC50 = 8.7 nM and had negligible binding affinity for the closely related 5-HT2B and 5-HT2C receptors. 10k was orally bioavailable in rats, dogs, and monkeys and had an acceptable safety profile. As a result, 10k was selected further evaluation and advanced into clinical development as a potential treatment for arterial thrombosis.

  DOI：

  10.1021/jm100044a