3-{3-tert-butylsulfanyl-1-[4-(6-methoxypyridin-3-yl)benzyl]-5-(quinoxalin-2-ylmethoxy)-1H-indol-2-yl}-2,2-dimethylpropionic acid | 950698-97-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 3-{3-tert-butylsulfanyl-1-[4-(6-methoxypyridin-3-yl)benzyl]-5-(quinoxalin-2-ylmethoxy)-1H-indol-2-yl}-2,2-dimethylpropionic acid
• 英文别名: 3-[3-Tert-butylsulfanyl-1-[[4-(6-methoxypyridin-3-yl)phenyl]methyl]-5-(quinoxalin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoic acid
• CAS: 950698-97-2
• 化学式: C₃₉H₄₀N₄O₄S
• 分子量: 660.837
• InChiKey: VILIXWVCAGLOCT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.5
• 重原子数：
  48
• 可旋转键数：
  12
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  125
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  2-甲基喹喔啉 在 lithium hydroxide monohydrate 、 三氯异氰尿酸 、 caesium carbonate 作用下， 以 四氢呋喃 、 甲醇 、 氯仿 、 水 、 乙腈 为溶剂， 反应 17.5h， 生成 3-{3-tert-butylsulfanyl-1-[4-(6-methoxypyridin-3-yl)benzyl]-5-(quinoxalin-2-ylmethoxy)-1H-indol-2-yl}-2,2-dimethylpropionic acid
  参考文献：
  名称：

  5-Lipoxygenase-Activating Protein (FLAP) Inhibitors. Part 4: Development of 3-[3-tert-Butylsulfanyl-1-[4-(6-ethoxypyridin-3-yl)benzyl]-5-(5-methylpyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethylpropionic Acid (AM803), a Potent, Oral, Once Daily FLAP Inhibitor

  摘要：

  The potent 5-lipoxygenase-activating protein (FLAP) inhibitor 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxypyridin-3-yl)benzyl]-5-(5-methylpyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethylpropionic acid 11cc is described (AM803, now GSK2190915). Building upon AM103 (1) (Hutchinson et al. J. Med Chem. 2009, 52, 5803-5815; Stock et al. Bioorg. Med. Chem. Lett. 2010, 20, 213-217; Stock et al. Bioorg. Med. Chem. Lett. 2010, 20, 4598-4601), SAR studies centering around the pyridine moiety led to the discovery of compounds that exhibit significantly increased potency in a human whole blood assay measuring LTB4 inhibition with longer drug preincubation times (15 min vs S h). Further studies identified 11cc with a potency of 2.9 nM in FLAP binding, an IC50 of 76 nM for inhibition of LTB4 in human blood (5 h incubation) and excellent preclinical toxicology and pharmacoldnetics in rat and dog. 11cc also demonstrated an extended pharmacodynamic effect in a rodent bronchoalveolar lavage (BAL) model. This compound has successfully completed phase 1 clinical studies in healthy volunteers and is currently undergoing phase 2 trials in asthmatic patients.

  DOI：

  10.1021/jm2008369

文献信息

• 5-LIPOXYGENASE-ACTIVATING PROTEIN (FLAP) INHIBITORS
  申请人：Hutchinson Howard John

  公开号：US20070219206A1

  公开（公告）日：2007-09-20

  Described herein are compounds and pharmaceutical compositions containing such compounds, which modulate the activity of 5-lipoxygenase-activating protein (FLAP). Also described herein are methods of using such FLAP modulators, alone and in combination with other compounds, for treating respiratory, cardiovascular, and other leukotriene-dependent or leukotriene mediated conditions or diseases.

  本文描述了一些化合物和含有这些化合物的制药组合物，这些化合物可以调节5-脂氧合酶激活蛋白（FLAP）的活性。本文还描述了使用这种FLAP调节剂的方法，单独或与其他化合物结合，用于治疗呼吸系统、心血管系统和其他依赖于白三烯或介导白三烯的疾病或病症。
• [EN] 5-LIPOXYGENASE-ACTIVATING PROTEIN (FLAP) INHIBITORS<br/>[FR] INHIBITEURS DE PROTÉINE FLAP (5-LIPOXYGENASE-ACTIVATING PROTEIN)
  申请人：AMIRA PHARMACEUTICALS INC

  公开号：WO2008137609A1

  公开（公告）日：2008-11-13

  [EN] Described herein are compounds and pharmaceutical compositions containing such compounds, which modulate the activity of 5-lipoxygenase-activating protein (FLAP). Also described herein are methods of using such FLAP modulators, alone and in combination with other compounds, for treating respiratory, cardiovascular, and other leukotriene-dependent or leukotriene mediated conditions or diseases.
  [FR] La présente invention concerne des composés et des compositions pharmaceutiques contenant de telles compositions, qui modulent l'activité de la protéine FLAP (5-Lipoxygenase-Activating Protein = protéine activant la 5-lipoxygénase). L'invention concerne également des procédés pour l'utilisation de tels modulateurs de la FLAP, seuls ou en association avec d'autres composés, pour le traitement d'états ou d'affections respiratoires, cardiovasculaires, ou autrement dépendants des leukotriènes ou découlant d'une médiation par les leukotriènes.
• 5-Lipoxygenase-Activating Protein (FLAP) Inhibitors. Part 4: Development of 3-[3-<i>tert</i>-Butylsulfanyl-1-[4-(6-ethoxypyridin-3-yl)benzyl]-5-(5-methylpyridin-2-ylmethoxy)-1<i>H</i>-indol-2-yl]-2,2-dimethylpropionic Acid (AM803), a Potent, Oral, Once Daily FLAP Inhibitor
  作者：Nicholas S. Stock、Gretchen Bain、Jasmine Zunic、Yiwei Li、Jeannie Ziff、Jeffrey Roppe、Angelina Santini、Janice Darlington、Pat Prodanovich、Christopher D. King、Christopher Baccei、Catherine Lee、Haojing Rong、Charles Chapman、Alex Broadhead、Dan Lorrain、Lucia Correa、John H. Hutchinson、Jilly F. Evans、Peppi Prasit

  DOI：10.1021/jm2008369

  日期：2011.12.8

  The potent 5-lipoxygenase-activating protein (FLAP) inhibitor 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxypyridin-3-yl)benzyl]-5-(5-methylpyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethylpropionic acid 11cc is described (AM803, now GSK2190915). Building upon AM103 (1) (Hutchinson et al. J. Med Chem. 2009, 52, 5803-5815; Stock et al. Bioorg. Med. Chem. Lett. 2010, 20, 213-217; Stock et al. Bioorg. Med. Chem. Lett. 2010, 20, 4598-4601), SAR studies centering around the pyridine moiety led to the discovery of compounds that exhibit significantly increased potency in a human whole blood assay measuring LTB4 inhibition with longer drug preincubation times (15 min vs S h). Further studies identified 11cc with a potency of 2.9 nM in FLAP binding, an IC50 of 76 nM for inhibition of LTB4 in human blood (5 h incubation) and excellent preclinical toxicology and pharmacoldnetics in rat and dog. 11cc also demonstrated an extended pharmacodynamic effect in a rodent bronchoalveolar lavage (BAL) model. This compound has successfully completed phase 1 clinical studies in healthy volunteers and is currently undergoing phase 2 trials in asthmatic patients.