1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl-3-[3-tert-butylsulfanyl-5-(pyridine-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester | 1190361-74-0

• 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: 1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl-3-[3-tert-butylsulfanyl-5-(pyridine-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester
• 英文别名: Ethyl 3-[3-tert-butylsulfanyl-5-(pyridin-2-ylmethoxy)-1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]indol-2-yl]-2,2-dimethylpropanoate
• CAS: 1190361-74-0
• 化学式: C₃₈H₄₉BN₂O₅S
• 分子量: 656.694
• InChiKey: VXRKXCVQJHSXNW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.99
• 重原子数：
  47
• 可旋转键数：
  13
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  97.1
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl-3-[3-tert-butylsulfanyl-5-(pyridine-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester 在 间氯过氧苯甲酸 作用下， 生成
  参考文献：
  名称：

  [EN] REDUCTION OF PRO-INFLAMMATORY HDL USING A LEUKOTRIENE INHIBITOR
  [FR] RÉDUCTION DE HDL PRO-INFLAMMATOIRE À L'AIDE D'UN INHIBITEUR DE LEUCOTRIÈNE

  摘要：

  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。

  公开号：

  WO2018152405A1
• 作为产物：
  描述：

  1-bromobenzyl-3-[3-tert-butylsulfanyl-5-(pyridine-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester 、 联硼酸频那醇酯 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 potassium acetate 作用下， 以 1,4-二氧六环 为溶剂， 反应 6.0h， 以100%的产率得到1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl-3-[3-tert-butylsulfanyl-5-(pyridine-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester
  参考文献：
  名称：

  5-Lipoxygenase-Activating Protein Inhibitors: Development 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 (AM103)

  摘要：

  The potent and selective 5-lipoxygenase-activating protein leukotriene synthesis inhibitor 3-[3-tert-butyl-sulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethylpropionic acid (11j) is described. Lead optimization was designed to afford compounds with superior in vitro and in vivo inhibition of leukotriene synthesis in addition to having excellent pharmacokinetics and safety in rats and dogs. The key structural features of these new compounds are incorporation of heterocycles on the indole N-benzyl substituent and replacement of the quinoline group resulting in compounds with excellent in vitro and in vim activities, superior pharmacokinetics, and improved physical properties. The methoxypyridine derivative 11j has an IC50 of 4.2 nM in a 5-lipoxygenase-activating protein (FLAP) binding assay, an IC50 of 349 nM in the human blood LTB4 inhibition assay, and is efficacious in a murine ovalbumin model of allergen-induced asthma. Compound 11j was selected for clinical development and has successfully completed phase I trials in healthy volunteers.

  DOI：

  10.1021/jm900945d

文献信息

• [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 Inhibitors: Development of 3-[3-<i>tert</i>-Butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1<i>H</i>-indol-2-yl]-2,2-dimethyl-propionic Acid (AM103)
  作者：John H. Hutchinson、Yiwei Li、Jeannie M. Arruda、Christopher Baccei、Gretchen Bain、Charles Chapman、Lucia Correa、Janice Darlington、Christopher D. King、Catherine Lee、Dan Lorrain、Pat Prodanovich、Haojing Rong、Angelina Santini、Nicholas Stock、Peppi Prasit、Jilly F. Evans

  DOI：10.1021/jm900945d

  日期：2009.10.8

  The potent and selective 5-lipoxygenase-activating protein leukotriene synthesis inhibitor 3-[3-tert-butyl-sulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethylpropionic acid (11j) is described. Lead optimization was designed to afford compounds with superior in vitro and in vivo inhibition of leukotriene synthesis in addition to having excellent pharmacokinetics and safety in rats and dogs. The key structural features of these new compounds are incorporation of heterocycles on the indole N-benzyl substituent and replacement of the quinoline group resulting in compounds with excellent in vitro and in vim activities, superior pharmacokinetics, and improved physical properties. The methoxypyridine derivative 11j has an IC50 of 4.2 nM in a 5-lipoxygenase-activating protein (FLAP) binding assay, an IC50 of 349 nM in the human blood LTB4 inhibition assay, and is efficacious in a murine ovalbumin model of allergen-induced asthma. Compound 11j was selected for clinical development and has successfully completed phase I trials in healthy volunteers.