3-[1-[4-(6-ethoxypyridin-3-yl)benzyl]-5-(5-methylpyridin-2-ylmethoxy)-3-phenylacetyl-1H-indol-2-yl]-2,2-dimethylpropionic acid | 950698-76-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 3-[1-[4-(6-ethoxypyridin-3-yl)benzyl]-5-(5-methylpyridin-2-ylmethoxy)-3-phenylacetyl-1H-indol-2-yl]-2,2-dimethylpropionic acid
• 英文别名: 3-[1-[[4-(6-Ethoxypyridin-3-yl)phenyl]methyl]-5-[(5-methylpyridin-2-yl)methoxy]-3-(2-phenylacetyl)indol-2-yl]-2,2-dimethylpropanoic acid
• CAS: 950698-76-7
• 化学式: C₄₂H₄₁N₃O₅
• 分子量: 667.805
• InChiKey: LVKNTVIWVXRKPM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.6
• 重原子数：
  50
• 可旋转键数：
  14
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  104
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  2,5-二甲基吡啶 在 盐酸 、 aluminum (III) chloride 、 氯化亚砜 、 lithium hydroxide monohydrate 、 水 、 caesium carbonate 、 间氯过氧苯甲酸 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 氯仿 、 水 、 1,2-二氯乙烷 、 乙腈 为溶剂， 反应 68.0h， 生成 3-[1-[4-(6-ethoxypyridin-3-yl)benzyl]-5-(5-methylpyridin-2-ylmethoxy)-3-phenylacetyl-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。