3-[3-tert-butylsulfanyl-1-[4-(2-ethoxy-thiazol-4-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid

• 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-[3-tert-butylsulfanyl-1-[4-(2-ethoxy-thiazol-4-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid
• 英文别名: 3-[3-Tert-butylsulfanyl-1-[[4-(2-ethoxy-1,3-thiazol-4-yl)phenyl]methyl]-5-[(5-methylpyridin-2-yl)methoxy]indol-2-yl]-2,2-dimethylpropanoic acid
• 化学式: C₃₆H₄₁N₃O₄S₂
• 分子量: 643.871
• InChiKey: JFNPTHBQIWJQNK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8
• 重原子数：
  45
• 可旋转键数：
  13
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  140
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  2,5-二甲基吡啶 在 盐酸 、 四(三苯基膦)钯 、 氯化亚砜 、 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 lithium hydroxide monohydrate 、 potassium acetate 、 potassium carbonate 、 caesium carbonate 、 间氯过氧苯甲酸 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 乙二醇二甲醚 、 氯仿 、 水 、 乙腈 为溶剂， 反应 87.0h， 生成 3-[3-tert-butylsulfanyl-1-[4-(2-ethoxy-thiazol-4-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic 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 H. John

  公开号：US20070105866A1

  公开（公告）日：2007-05-10

  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.

  本发明描述了调节5-脂氧合酶激活蛋白(FLAP)活性的化合物和含有该化合物的药物组合物。本发明还描述了单独使用和与其他化合物联合使用FLAP调节剂，用于治疗呼吸系统、心血管系统和其他白三烯依赖性或白三烯介导的状况或疾病。
• [EN] REDUCTION OF PRO-INFLAMMATORY HDL USING A LEUKOTRIENE INHIBITOR<br/>[FR] RÉDUCTION DE HDL PRO-INFLAMMATOIRE À L'AIDE D'UN INHIBITEUR DE LEUCOTRIÈNE
  申请人：AUTOIMMUNE PHARMA LLC

  公开号：WO2018152405A1

  公开（公告）日：2018-08-23

  A method involving the administration of a therapeutically effective amount of a leukotriene inhibitor, a pharmaceutically acceptable salt, a pharmaceutically acceptable N-oxide, a pharmaceutically active metabolite, a pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof to a human for reducing a level of pro-inflammatory HDL in the human. Various examples of leukotriene inhibitors, including 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxy-pyridin- 3-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2, 2-dimethyl-propionic acid, are disclosed for administration for the reduction of pro-inflammatory HDL in a human. Reduction of pro-inflammatory HDL by the leukotriene inhibitor may include conversion of at least a portion of pro-inflammatory HDL to anti-inflammatory HDL.

  一种方法，涉及给人类施用治疗有效量的白细胞三烯抑制剂、药物可接受的盐、药物可接受的N-氧化物、药物活性代谢物、药物可接受的的前药或其药物可接受的溶剂化物，以降低人类中的前炎症高密度脂蛋白(HDL)水平。公开了各种白细胞三烯抑制剂，包括3-[3-叔丁基硫基-1-[4-(6-乙氧基-吡啶-3-基)-苄基]-5-(5-甲基-吡啶-2-基甲氧基)-1H-吲哚-2-基]-2,2-二甲基丙酸，用于施用以降低人类中的前炎症HDL。通过白细胞三烯抑制剂降低前炎症HDL可能包括将至少部分前炎症HDL转化为抗炎症HDL。
• 5-Lipoxygenase-Activating Protein (FLAP) Inhibitors
  申请人：Panmira Pharmaceuticals, Inc.

  公开号：US20130102636A1

  公开（公告）日：2013-04-25

  A method for treating a human comprises administering a therapeutically effective amount of 3-[3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid or a pharmaceutically acceptable salt or a pharmaceutically acceptable N-oxide thereof, to the human in need.

  一种治疗人类的方法包括向需要治疗的人类施用治疗有效量的3-[3-叔丁基磺酰基-1-[4-(6-甲氧基吡啶-3-基)-苄基]-5-(吡啶-2-基甲氧基)-1H-吲哚-2-基]-2,2-二甲基丙酸或其药学上可接受的盐或药学上可接受的N-氧化物。
• 5-LIPOXGENASE-ACTIVATING PROTEIN (FLAP) INHIBITORS
  申请人：Panmira Pharmaceuticals, LLC

  公开号：US20140018394A1

  公开（公告）日：2014-01-16

  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药物组合物，可调节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组合，用于治疗呼吸系统、心血管系统和其他依赖或介导白三烯的疾病或病情。
• 5-lipoxygenase-activating protein (FLAP) inhibitors
  申请人：Amira Pharmaceuticals, Inc.

  公开号：EP2404904A1

  公开（公告）日：2012-01-11

  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.

  本文描述了调节 5-脂氧合酶激活蛋白（FLAP）活性的化合物和含有此类化合物的药物组合物。本文还描述了使用此类 FLAP 调节剂（单独使用或与其他化合物结合使用）治疗呼吸系统、心血管和其他白三烯依赖性或白三烯介导的病症或疾病的方法。