3-methoxy-N-{3-(1-methyl-1H-pyrazol-5-yl)-4-[2-(4-(methylsulfonyl)piperazin-1-yl)ethoxy]phenyl}benzamide | 1227254-39-8

• 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: 3-methoxy-N-{3-(1-methyl-1H-pyrazol-5-yl)-4-[2-(4-(methylsulfonyl)piperazin-1-yl)ethoxy]phenyl}benzamide
• 英文别名: 3-methoxy-N-[3-(2-methylpyrazol-3-yl)-4-[2-(4-methylsulfonylpiperazin-1-yl)ethoxy]phenyl]benzamide
• CAS: 1227254-39-8
• 化学式: C₂₅H₃₁N₅O₅S
• 分子量: 513.618
• InChiKey: BNCLJFZXGJBOMA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  36
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  114
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  1-甲烷磺酰哌嗪 、 N-[4-(2-bromo-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.33h， 生成 3-methoxy-N-{3-(1-methyl-1H-pyrazol-5-yl)-4-[2-(4-(methylsulfonyl)piperazin-1-yl)ethoxy]phenyl}benzamide
  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

文献信息

• Discovery and Structure−Activity Relationship of 3-Methoxy-<i>N</i>-(3-(1-methyl-1<i>H</i>-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide (APD791): A Highly Selective 5-Hydroxytryptamine_2A Receptor Inverse Agonist for the Treatment of Arterial Thrombosis
  作者：Yifeng Xiong、Bradley R. Teegarden、Jin-Sun Karoline Choi、Sonja Strah-Pleynet、Marc Decaire、Honnappa Jayakumar、Peter I. Dosa、Martin D. Casper、Lan Pham、Konrad Feichtinger、Brett Ullman、John Adams、Diane Yuskin、John Frazer、Michael Morgan、Abu Sadeque、Weichao Chen、Robert R. Webb、Daniel T. Connolly、Graeme Semple、Hussien Al-Shamma

  DOI：10.1021/jm100044a

  日期：2010.6.10

  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.