(R)-4-[4-(5-{1-[2-(2-tert-butoxycarbonylamino-4-methyl-pentanoylamino)acetyl]-piperidin-4-yl}-1-methyl-1H-pyrazol-3-yl)-2,3-dichloro-phenoxymethyl]benzoic acid methyl ester | 515846-55-6

• 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: (R)-4-[4-(5-{1-[2-(2-tert-butoxycarbonylamino-4-methyl-pentanoylamino)acetyl]-piperidin-4-yl}-1-methyl-1H-pyrazol-3-yl)-2,3-dichloro-phenoxymethyl]benzoic acid methyl ester
• 英文别名: (R)-4-[4-(5-{1-[2-(2-tert-butoxycarbonylamino-4-methylpentanoylamino)acetyl]piperidin-4-yl}-1-methyl-1H-pyrazol-3-yl)-2,3-dichlorophenoxymethyl]benzoic acid methyl ester
• CAS: 515846-55-6
• 化学式: C₃₇H₄₇Cl₂N₅O₇
• 分子量: 744.715
• InChiKey: OJHNJBAYLLMXPO-MUUNZHRXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.52
• 重原子数：
  51.0
• 可旋转键数：
  12.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.49
• 拓扑面积：
  141.09
• 氢给体数：
  2.0
• 氢受体数：
  9.0

反应信息

• 作为反应物：
  描述：

  (R)-4-[4-(5-{1-[2-(2-tert-butoxycarbonylamino-4-methyl-pentanoylamino)acetyl]-piperidin-4-yl}-1-methyl-1H-pyrazol-3-yl)-2,3-dichloro-phenoxymethyl]benzoic acid methyl ester 在 lithium hydroxide 作用下， 以 四氢呋喃 为溶剂， 以39%的产率得到(R)-4-[4-(5-{1-[2-(2-tert-butoxycarbonylamino-4-methyl-pentanoylamino)acetyl]-piperidin-4-yl}-1-methyl-1H-pyrazol-3-yl)-2,3-dichloro-phenoxymethyl]benzoic acid
  参考文献：
  名称：

  Discovery of a Potent Small Molecule IL-2 Inhibitor through Fragment Assembly

  摘要：

  Using a site-directed fragment discovery method called tethering, we have identified a 60 nM small molecule antagonist of a cytokine/receptor interaction (IL-2/IL2Ralpha) with cell-based activity. Starting with a low micromolar hit, we employed a combination of tethering, structural biology, and computational analysis to design a focused set of 20 compounds. Eight of these compounds were at least 5-fold more active than the original hit. One of these compounds showed a 50-fold enhancement and represents the highest affinity inhibitor reported against this protein-protein target class. This method of coupling selected fragments with a low micromolar hit shows great potential for generating high-affinity lead compounds.

  DOI：

  10.1021/ja034247i
• 作为产物：
  描述：

  2,3-dichloro-4-triisopropylsilanyloxy-benzoic acid 在 bis-triphenylphosphine-palladium(II) chloride 、 copper(l) iodide 、 草酰氯 、 四丁基氟化铵 、 potassium carbonate 、 三乙胺 、 N,N-二甲基甲酰胺 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 5.17h， 生成 (R)-4-[4-(5-{1-[2-(2-tert-butoxycarbonylamino-4-methyl-pentanoylamino)acetyl]-piperidin-4-yl}-1-methyl-1H-pyrazol-3-yl)-2,3-dichloro-phenoxymethyl]benzoic acid methyl ester
  参考文献：
  名称：

  Integrating Fragment Assembly and Biophysical Methods in the Chemical Advancement of Small-Molecule Antagonists of IL-2:  An Approach for Inhibiting Protein−Protein Interactions

  摘要：

  Fragment assembly has shown promise for discovering small-molecule antagonists for difficult targets, including protein-protein interactions. Here, we describe a process for identifying a 60 nM inhibitor of the interleukin-2 (IL-2)/IL-2 receptor (IL-2Ralpha) interaction. By use of fragment-based approaches, a compound with millimolar affinity was evolved to a hit series with low micromolar activity, and these compounds were optimized into a lead series with nanomolar affinity. Fragment assembly was useful not only for hit identification, but also for lead optimization. Throughout the discovery process, biophysical methods and structural biology demonstrated that compounds bound reversibly to IL-2 at the IL-2 receptor binding site.

  DOI：

  10.1021/jm049967u