(S)-2-(2-acetamidoacetamido)-6-amino-N-((S)-1-amino-4-methyl-1-oxopentan-2-yl)hexanamide | 66127-73-9

• 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
• 英文名称: (S)-2-(2-acetamidoacetamido)-6-amino-N-((S)-1-amino-4-methyl-1-oxopentan-2-yl)hexanamide
• 英文别名: N-Acetylglycyl-L-lysyl-L-leucinamide；(2S)-2-[(2-acetamidoacetyl)amino]-6-amino-N-[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]hexanamide
• CAS: 66127-73-9
• 化学式: C₁₆H₃₁N₅O₄
• 分子量: 357.453
• InChiKey: VYYWFDFUTHBYHU-STQMWFEESA-N

物化性质

• 沸点：
  746.8±60.0 °C(Predicted)
• 密度：
  1.130±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -1.3
• 重原子数：
  25
• 可旋转键数：
  12
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  156
• 氢给体数：
  5
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  NAlpha-BOC-Nε-FMOC-L-赖氨酸 在 哌啶 、 N,N-二异丙基乙胺 、 三氟乙酸 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 28.0h， 生成 (S)-2-(2-acetamidoacetamido)-6-amino-N-((S)-1-amino-4-methyl-1-oxopentan-2-yl)hexanamide
  参考文献：
  名称：

  Identification of Inhibitors of Thrombospondin 1 Activation of TGF-β

  摘要：

  TGF-beta has been a target of interest for the treatment of fibrotic diseases and certain cancers. Approaches to target TGF-beta include antagonists of the active ligand or TGF-beta receptor kinase activity. These approaches have failed in clinical trials due to a lack of effectiveness and a limited therapeutic window. In this context, newer and more selective approaches to target TGF-beta are needed. We previously reported that the matricellular protein, thrombospondin 1, activates the latent TGF-beta complex and that antagonism of this pathway using tri/tetrapeptides in various animal models reduces fibrosis. The tripeptide, SRI-31277 (1), is effective in vivo but has a short plasma half life (0.2 h). Herein we describe the design and synthesis SRI-31277 analogs, specifically smaller peptides that retain potency and have improved bioavailability. We identified SRI-35241 (36) with a single chiral center, which blocks TGF-beta activation (pIC(50) = 8.12 nM) and has a plasma half life of 1.8 h (iv).

  DOI：

  10.1021/acsmedchemlett.9b00540

文献信息

• Identification of Inhibitors of Thrombospondin 1 Activation of TGF-β
  作者：Mark J. Suto、Vandana Gupta、Bini Mathew、Wei Zhang、Manuel A. Pallero、Joanne E. Murphy-Ullrich

  DOI：10.1021/acsmedchemlett.9b00540

  日期：2020.6.11

  TGF-beta has been a target of interest for the treatment of fibrotic diseases and certain cancers. Approaches to target TGF-beta include antagonists of the active ligand or TGF-beta receptor kinase activity. These approaches have failed in clinical trials due to a lack of effectiveness and a limited therapeutic window. In this context, newer and more selective approaches to target TGF-beta are needed. We previously reported that the matricellular protein, thrombospondin 1, activates the latent TGF-beta complex and that antagonism of this pathway using tri/tetrapeptides in various animal models reduces fibrosis. The tripeptide, SRI-31277 (1), is effective in vivo but has a short plasma half life (0.2 h). Herein we describe the design and synthesis SRI-31277 analogs, specifically smaller peptides that retain potency and have improved bioavailability. We identified SRI-35241 (36) with a single chiral center, which blocks TGF-beta activation (pIC(50) = 8.12 nM) and has a plasma half life of 1.8 h (iv).