(5,5-二氧化物-4H-噻吩并[3,2-c][1]苯并噻喃-2-基)[4-(4-甲氧基苯基)-1-哌嗪基]甲酮 | 890819-86-0

• 物质功能分类: 生物化工 - 抑制剂
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 中文名称: (5,5-二氧化物-4H-噻吩并[3,2-c][1]苯并噻喃-2-基)[4-(4-甲氧基苯基)-1-哌嗪基]甲酮
• 英文名称: ML349
• 英文别名: 1-[(5,5-dioxido-4H-thieno[3,2-c]thiochromen-2-yl)carbonyl]-4-(4-methoxyphenyl)piperazine；(5,5-dioxo-4H-thieno[3,2-c]thiochromen-2-yl)-[4-(4-methoxyphenyl)piperazin-1-yl]methanone
• CAS: 890819-86-0
• 化学式: C₂₃H₂₂N₂O₄S₂
• 分子量: 454.571
• InChiKey: YVIJPELUPZUEJX-UHFFFAOYSA-N

物化性质

• 溶解度：
  DMSO：20 mg/mL（44.00 mM；需要超声波）

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  31
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  104
• 氢给体数：
  0
• 氢受体数：
  6

制备方法与用途

生物活性

ML349 是一个有效且特异的酰基蛋白硫酯酶 2 (APT-2) 抑制剂，其 Ki 值为 120 nM。它也是 LYPLA2 的抑制剂，IC50 值为 144 nM。

靶点

• Ki: 120 nM (APT-2)
• IC50: 144 nM (LYPLA2)

体外研究

ML349 是酰基蛋白硫酯酶 1 和 2 (APT-1 和 APT-2) 的抑制剂，其 Ki 值分别为 >10,000 和 120±20 nM。它也是 LYPLA1 和 LYPLA2 的抑制剂，IC50 值分别为 >3,000 和 144 nM。

ML348 和 ML349 并未减少细胞活力，但它们会导致 NRAS 突变细胞中轻微激活 AKT。

反应信息

• 作为产物：
  描述：

  1-(4-甲氧基苯基)哌嗪 、 4H-thieno[3,2-c]thiochromene-2-carboxylic acid 5,5-dioxide 在 4-二甲氨基吡啶 、 1,2-二氯乙烷 作用下， 反应 12.0h， 以87%的产率得到(5,5-二氧化物-4H-噻吩并[3,2-c][1]苯并噻喃-2-基)[4-(4-甲氧基苯基)-1-哌嗪基]甲酮
  参考文献：
  名称：

  Confirming Target Engagement for Reversible Inhibitors in Vivo by Kinetically Tuned Activity-Based Probes

  摘要：

  The development of small-molecule inhibitors for perturbing enzyme function requires assays to confirm that the inhibitors interact with their enzymatic targets in vivo. Determining target engagement in vivo can be particularly challenging for poorly characterized enzymes that lack known biomarkers (e.g., endogenous substrates and products) to report on their inhibition. Here, we describe a competitive activity-based protein profiling (ABPP) method for measuring the binding of reversible inhibitors to enzymes in animal models. Key to the success of this approach is the use of activity-based probes that show tempered rates of reactivity with enzymes, such that competition for target engagement with reversible inhibitors can be measured in vivo. We apply the competitive ABPP strategy to evaluate a newly described class of piperazine amide reversible inhibitors for the serine hydrolases LYPLA1 and LYPLA2, two enzymes for which selective, in vivo active inhibitors are lacking. Competitive ABPP identified individual piperazine amides that selectively inhibit LYPLA1 or LYPLA2 in mice. In summary, competitive ABPP adapted to operate with moderately reactive probes can assess the target engagement of reversible inhibitors in animal models to facilitate the discovery of small-molecule probes for characterizing enzyme function in vivo.

  DOI：

  10.1021/ja303400u

文献信息

• Confirming Target Engagement for Reversible Inhibitors in Vivo by Kinetically Tuned Activity-Based Probes
  作者：Alexander Adibekian、Brent R. Martin、Jae Won Chang、Ku-Lung Hsu、Katsunori Tsuboi、Daniel A. Bachovchin、Anna E. Speers、Steven J. Brown、Timothy Spicer、Virneliz Fernandez-Vega、Jill Ferguson、Peter S. Hodder、Hugh Rosen、Benjamin F. Cravatt

  DOI：10.1021/ja303400u

  日期：2012.6.27

  The development of small-molecule inhibitors for perturbing enzyme function requires assays to confirm that the inhibitors interact with their enzymatic targets in vivo. Determining target engagement in vivo can be particularly challenging for poorly characterized enzymes that lack known biomarkers (e.g., endogenous substrates and products) to report on their inhibition. Here, we describe a competitive activity-based protein profiling (ABPP) method for measuring the binding of reversible inhibitors to enzymes in animal models. Key to the success of this approach is the use of activity-based probes that show tempered rates of reactivity with enzymes, such that competition for target engagement with reversible inhibitors can be measured in vivo. We apply the competitive ABPP strategy to evaluate a newly described class of piperazine amide reversible inhibitors for the serine hydrolases LYPLA1 and LYPLA2, two enzymes for which selective, in vivo active inhibitors are lacking. Competitive ABPP identified individual piperazine amides that selectively inhibit LYPLA1 or LYPLA2 in mice. In summary, competitive ABPP adapted to operate with moderately reactive probes can assess the target engagement of reversible inhibitors in animal models to facilitate the discovery of small-molecule probes for characterizing enzyme function in vivo.