N-[(2S)-1-[[(2S,3S)-1-[[2-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-2-oxoethyl]amino]-3-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]-1H-indole-4-carboxamide | 1268717-58-3

• 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: N-[(2S)-1-[[(2S,3S)-1-[[2-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-2-oxoethyl]amino]-3-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]-1H-indole-4-carboxamide
• CAS: 1268717-58-3
• 化学式: C₃₅H₅₆N₁₀O₆
• 分子量: 712.893
• InChiKey: SDJQHIRHSDSECQ-RFCCKVQESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  51
• 可旋转键数：
  21
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  269
• 氢给体数：
  9
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  吲哚-4-羧酸 、 spiro{(1',4'-anhydro-2',3',5'-tri-O-benzyl-L-arabinitol)-1',4-[(S)-(9H-fluoren-9-yl)methyl 2-formylpyrrolidine-1-carboxylate]} 在 哌啶 、 2,6-二甲基吡啶 、 1-羟基苯并三唑 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 茴香硫醚 、 水 、 1,2-乙二硫醇 、 三氟乙酸 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 4.33h， 生成 N-[(2S)-1-[[(2S,3S)-1-[[2-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-2-oxoethyl]amino]-3-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]-1H-indole-4-carboxamide
  参考文献：
  名称：

  Potent Agonists of the Protease Activated Receptor 2 (PAR₂)

  摘要：

  Novel peptidomimetic pharmacophores to PAR(2) were designed based on the known activating peptide SLIGRL-NH2. A set of 15 analogues was evaluated with a model cell line (16HBE14o-) that highly expresses PAR(2). Cells exposed to the PAR2 activating peptide with N-terminal 2-furoyl modification (2-furoyl-LIGRLO-NH2) initiated increases in intracellular calcium concentration. ([Ca2+](i) EC50 = 0.84 mu M) and in vitro physiological responses as measured by the xCELLigence real time cell analyzer (RTCA EC50 = 138 nM). We discovered two selective PAR(2) agonists with comparable potency: compound 1 (2-aminothiazol-4-yl; Ca2+ EC50 = 1.77 mu M, RTCA EC50 = 142 nM) and compound 2 (6-aminonicotinyl; Ca2+ EC50 = 2.60 mu M, RTCA EC50 = 311 nM). Unlike the previously described agonist, these novel agonists are devoid of the metabolically unstable 2-furoyl modification and thus provide potential advantages for PAR2 peptide design for in vitro and in vivo studies. The novel compounds described herein also serve as a starting point for structure activity relationship (SAR) design and are, for the fist time, evaluated via a unique high throughput in vitro physiological assay. Together these will lead to discovery of more potent agonists and antagonists of PAR(2).

  DOI：

  10.1021/jm1013049

文献信息

• Potent Agonists of the Protease Activated Receptor 2 (PAR₂)
  作者：Scott Boitano、Andrea N. Flynn、Stephanie M. Schulz、Justin Hoffman、Theodore J. Price、Josef Vagner

  DOI：10.1021/jm1013049

  日期：2011.3.10

  Novel peptidomimetic pharmacophores to PAR(2) were designed based on the known activating peptide SLIGRL-NH2. A set of 15 analogues was evaluated with a model cell line (16HBE14o-) that highly expresses PAR(2). Cells exposed to the PAR2 activating peptide with N-terminal 2-furoyl modification (2-furoyl-LIGRLO-NH2) initiated increases in intracellular calcium concentration. ([Ca2+](i) EC50 = 0.84 mu M) and in vitro physiological responses as measured by the xCELLigence real time cell analyzer (RTCA EC50 = 138 nM). We discovered two selective PAR(2) agonists with comparable potency: compound 1 (2-aminothiazol-4-yl; Ca2+ EC50 = 1.77 mu M, RTCA EC50 = 142 nM) and compound 2 (6-aminonicotinyl; Ca2+ EC50 = 2.60 mu M, RTCA EC50 = 311 nM). Unlike the previously described agonist, these novel agonists are devoid of the metabolically unstable 2-furoyl modification and thus provide potential advantages for PAR2 peptide design for in vitro and in vivo studies. The novel compounds described herein also serve as a starting point for structure activity relationship (SAR) design and are, for the fist time, evaluated via a unique high throughput in vitro physiological assay. Together these will lead to discovery of more potent agonists and antagonists of PAR(2).