(2R,4'R,8'aR)-1-[2-[4-[[2-(2,4-二氯苯氧基)乙酰基]氨基]苯基]乙酰基]四氢-6'-氧代螺[吡咯烷-2,7'(6'H)-[2H]吡咯并[2,1-b][1,3]噻嗪]-4'-甲酰胺 | 894787-30-5

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 中文名称: (2R,4'R,8'aR)-1-[2-[4-[[2-(2,4-二氯苯氧基)乙酰基]氨基]苯基]乙酰基]四氢-6'-氧代螺[吡咯烷-2,7'(6'H)-[2H]吡咯并[2,1-b][1,3]噻嗪]-4'-甲酰胺
• 中文别名: (2R,4'R,8'AR)-1-[2-[4-[[2-(2,4-二氯苯氧基)乙酰基]氨基]苯基]乙酰基]四氢-6'-氧代螺[吡咯烷-2,7'(6'H)-[2H]吡咯并[2,1-B][1,3]噻嗪]-4'-甲酰胺
• 英文名称: ST2825
• 英文别名: (2R,4'R,8a'R)-1-(2-(4-(2-(2,4-dichlorophenoxy)acetamido)phenyl)acetyl)-6'-oxotetrahydro-2'H,6'H-spiro[pyrrolidine-2,7'-pyrrolo[2,1-b][1,3]thiazine]-4'-carboxamide；(4R,7R,8aR)-1'-[2-[4-[[2-(2,4-dichlorophenoxy)acetyl]amino]phenyl]acetyl]-6-oxospiro[3,4,8,8a-tetrahydro-2H-pyrrolo[2,1-b][1,3]thiazine-7,2'-pyrrolidine]-4-carboxamide
• CAS: 894787-30-5
• 化学式: C₂₇H₂₈Cl₂N₄O₅S
• 分子量: 591.515
• InChiKey: HBLHLJXFIPCEMW-ZJSFPPFMSA-N

物化性质

• 沸点：
  939.0±65.0 °C(Predicted)
• 密度：
  1.51±0.1 g/cm3(Predicted)
• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  39
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  147
• 氢给体数：
  2
• 氢受体数：
  6

制备方法与用途

生物活性

ST 2825 是一种特异的 MyD88 二聚化抑制剂。它能够干扰 MyD88 对 IRAK1 和 IRAK4 的募集，从而抑制 IL-1β 介导的 NF-κB 转录活性。

靶点

MyD88

体外研究

ST2825 通过干扰 MyD88 同源二聚化来阻断 IL-1R/TLR 信号传导。这种抑制作用呈浓度依赖性，在 5 μM ST2825 下约有 40% 的二聚化抑制效果，而在 10 μM ST2825 下则达到约 80%。

体内研究

ST2825 在口服给药后剂量依赖性地抑制了小鼠在注射 20 μg/kg IL-1β 前后的 IL-6 生产。实验中，动物分别以 50 到 200 mg/kg 的 ST2825 进行口服给药，结果显示，在 100 和 200 mg/kg 的剂量下，ST2825 显著抑制了由 IL-1β 引起的 IL-6 生产。

反应信息

• 作为产物：
  描述：

  (2R,4'R,8a'R)-1-[(9H-fluoren-9-ylmethoxy)carbonyl]-6'-oxotetrahydro-2'H-spiro[pyrrolidine-2,7'-pyrrole[2,1-b][1,3]thiazine]-4'-carboxylic acid 、 2-(2,6-二氯苯氧基)乙酰氯 、 Fmoc-(4-氨基苯基)乙酸 以9.3 mg的产率得到(2R,4'R,8'aR)-1-[2-[4-[[2-(2,4-二氯苯氧基)乙酰基]氨基]苯基]乙酰基]四氢-6'-氧代螺[吡咯烷-2,7'(6'H)-[2H]吡咯并[2,1-b][1,3]噻嗪]-4'-甲酰胺
  参考文献：
  名称：

  Design, Synthesis, and In Vitro Activity of Peptidomimetic Inhibitors of Myeloid Differentiation Factor 88

  摘要：

  We describe the design and synthesis of a peptidomimetic library derived from the heptapeptide Ac-RDVLPGT-NH(2), belonging to the Toll/IL-1 receptor (TIR) domain of the adaptor protein MyD88 and effective in inhibiting its homodimerization. The ability of the peptidomimetics to inhibit protein-protein interaction was assessed by yeast 2-hybrid assay and further validated in a mammalian cell system by evaluating the inhibition of NF-kappa B activation, a transcription factor downstream of MyD88 signaling pathway that allows production of essential effector molecules for immune and inflammatory responses.

  DOI：

  10.1021/jm070723u

文献信息

• Myd88 Homodimerization Inhibitors
  申请人：Carminati Paolo

  公开号：US20080064643A1

  公开（公告）日：2008-03-13

  The present invention relates to peptidic and peptidomimetic compounds with the formula (X − )AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 -AA 7 in which the various groups are defined in the description here below, which mimic a particular protein portion of MyD88, preventing its homodimerisation and interfering with its interaction with the TIR domain. The present invention also provides procedures for the preparation of said compounds, pharmaceutical compositions containing them and their use as medicaments, particularly for the treatment of inflammatory and autoimmune diseases.
• Design, Synthesis, and In Vitro Activity of Peptidomimetic Inhibitors of Myeloid Differentiation Factor 88
  作者：Nicola Fantò、Grazia Gallo、Andrea Ciacci、Mauro Semproni、Davide Vignola、Marco Quaglia、Valentina Bombardi、Domenico Mastroianni、M. Pia Zibella、Giancarlo Basile、Marica Sassano、Vito Ruggiero、Rita De Santis、Paolo Carminati

  DOI：10.1021/jm070723u

  日期：2008.3.13

  We describe the design and synthesis of a peptidomimetic library derived from the heptapeptide Ac-RDVLPGT-NH(2), belonging to the Toll/IL-1 receptor (TIR) domain of the adaptor protein MyD88 and effective in inhibiting its homodimerization. The ability of the peptidomimetics to inhibit protein-protein interaction was assessed by yeast 2-hybrid assay and further validated in a mammalian cell system by evaluating the inhibition of NF-kappa B activation, a transcription factor downstream of MyD88 signaling pathway that allows production of essential effector molecules for immune and inflammatory responses.