3-(4-((S)-3-methyl-2-(quinolin-6-ylmethylamino)butan-2-yl)-1H-1,2,3-triazol-1-yl)-1-(2,3,5,6-tetrafluorophenoxy)heptan-2-one | 1029431-36-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 3-(4-((S)-3-methyl-2-(quinolin-6-ylmethylamino)butan-2-yl)-1H-1,2,3-triazol-1-yl)-1-(2,3,5,6-tetrafluorophenoxy)heptan-2-one
• 英文别名: 3-[4-[(2S)-3-methyl-2-(quinolin-6-ylmethylamino)butan-2-yl]triazol-1-yl]-1-(2,3,5,6-tetrafluorophenoxy)heptan-2-one
• CAS: 1029431-36-4
• 化学式: C₃₀H₃₃F₄N₅O₂
• 分子量: 571.618
• InChiKey: YXKHZYNSINIHQT-FZNWDQQTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.2
• 重原子数：
  41
• 可旋转键数：
  13
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  81.9
• 氢给体数：
  1
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  2,3,5,6-四氟苯酚 在 potassium fluoride 、 copper(II) sulfate 、 sodium ascorbate 作用下， 以 水 、 N,N-二甲基甲酰胺 、 叔丁醇 为溶剂， 生成 3-(4-((S)-3-methyl-2-(quinolin-6-ylmethylamino)butan-2-yl)-1H-1,2,3-triazol-1-yl)-1-(2,3,5,6-tetrafluorophenoxy)heptan-2-one
  参考文献：
  名称：

  Tetrafluorophenoxymethyl ketone cruzain inhibitors with improved pharmacokinetic properties as therapeutic leads for Chagas’ disease

  摘要：

  Inhibition of the cysteine protease cruzain from Trypanosoma cruzi has been studied pre-clinically as a new chemotherapeutic approach to treat Chagas' disease. Efficacious effects of vinylsulfone-based cruzain inhibitors in animal models support this therapeutic hypothesis. More recently, substrate-activity screening was used to identify nonpeptidic tetrafluorophenoxymethyl ketone inhibitors of cruzain that showed promising efficacy in animal models. Herein we report efforts to further optimize the in vitro potency and in vivo pharmacokinetic properties of this new class of cruzain inhibitors. Through modifications of the P1, P2 and/or P3 positions, new analogs have been identified with reduced lipophilicity, enhanced potency, and improved oral exposure and bioavailability. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2015.06.066

文献信息

• Identification of a New Class of Nonpeptidic Inhibitors of Cruzain
  作者：Katrien Brak、Patricia S. Doyle、James H. McKerrow、Jonathan A. Ellman

  DOI：10.1021/ja710254m

  日期：2008.5.1

  inhibitors. The previously unexplored beta-chloro vinyl sulfone pharmacophore provided mechanistic insight that led to the development of potent irreversible acyl- and aryl-oxymethyl ketone cruzain inhibitors. For these inhibitors, potency did not solely depend on leaving group p K a, with 2,3,5,6-tetrafluorophenoxymethyl ketone 54 identified as one of the most potent inhibitors with a second-order inactivation

  Cruzain 是克氏锥虫的主要半胱氨酸蛋白酶，它是南美锥虫病的病原体，是开发新化疗的有希望的靶点。为了开发有效的 cruzain 非肽抑制剂，使用底物活性筛选 (SAS) 方法筛选最初设计用于靶向同源人蛋白酶组织蛋白酶 S 的蛋白酶底物库。接下来使用基于结构的设计来进一步改进底物通过在 cruzain 的 S3 口袋中引入额外的结合相互作用来提高切割效率。然后通过引入基于半胱氨​​酸蛋白酶机制的药效团将优化的底物转化为抑制剂。抑制剂 38 被确定是可逆的，即使它掺入了乙烯基砜药效团，该药效团已被充分证明可以对肽抑制剂产生不可逆的 cruzain 抑制作用。先前未探索的 β-氯乙烯基砜药效团提供了导致开发有效的不可逆酰基和芳基氧甲基酮 cruzain 抑制剂的机理洞察力。对于这些抑制剂，效力不仅仅取决于离去基团 p K a，2,3,5,6-四氟苯氧基甲基酮 54 被鉴定为最有效的抑制剂之一，其二级失活常数为