(R)-2-((R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)-3-(naphthalen-2-yl)propanoic acid | 1427425-55-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: (R)-2-((R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)-3-(naphthalen-2-yl)propanoic acid
• 英文别名: (2R)-2-[(4R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-3-naphthalen-2-ylpropanoic acid
• CAS: 1427425-55-5
• 化学式: C₁₈H₁₈O₅
• 分子量: 314.338
• InChiKey: LFUFTVUAMDTQTF-HUUCEWRRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  72.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (R)-2-((R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)-3-(naphthalen-2-yl)propanoic acid 、 Fmoc-Pbf-L-精氨酸 在 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 哌啶 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 以88%的产率得到(2R,3R)-N-[(2S)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-N',3-dihydroxy-2-(naphthalen-2-ylmethyl)butanediamide
  参考文献：
  名称：

  Optimization of Peptide Hydroxamate Inhibitors of Insulin-Degrading Enzyme Reveals Marked Substrate-Selectivity

  摘要：

  Insulin-degrading enzyme (IDE) is an atypical zinc-metallopeptidase that degrades insulin and the amyloid ss-protein and is strongly implicated in the pathogenesis of diabetes and Alzheimer's disease. We recently developed the first effective inhibitors of IDE, peptide hydroxamates that, while highly potent and selective, are relatively large (MW > 740) and difficult to synthesize. We present here a facile synthetic route that yields enantiomerically pure derivatives comparable in potency to the parent compounds. Through the generation of truncated variants, we identified a compound with significantly reduced size (MW = 455.5) that nonetheless retains good potency (k(i), = 78 +/- 11 nM) and selectivity for IDE. Notably, the potency of these inhibitors was found to vary as much as 60-fold in a substrate-specific manner, an unexpected finding for active site-directed inhibitors. Collectively, our findings demonstrate that potent, small-molecule IDE inhibitors can be developed that, in certain instances, can be highly substrate selective.

  DOI：

  10.1021/jm301280p

文献信息

• Optimization of Peptide Hydroxamate Inhibitors of Insulin-Degrading Enzyme Reveals Marked Substrate-Selectivity
  作者：Samer O. Abdul-Hay、Amy L. Lane、Thomas R. Caulfield、Clémence Claussin、Juliette Bertrand、Amandine Masson、Shakeel Choudhry、Abdul H. Fauq、Guhlam M. Maharvi、Malcolm A. Leissring

  DOI：10.1021/jm301280p

  日期：2013.3.28

  Insulin-degrading enzyme (IDE) is an atypical zinc-metallopeptidase that degrades insulin and the amyloid ss-protein and is strongly implicated in the pathogenesis of diabetes and Alzheimer's disease. We recently developed the first effective inhibitors of IDE, peptide hydroxamates that, while highly potent and selective, are relatively large (MW > 740) and difficult to synthesize. We present here a facile synthetic route that yields enantiomerically pure derivatives comparable in potency to the parent compounds. Through the generation of truncated variants, we identified a compound with significantly reduced size (MW = 455.5) that nonetheless retains good potency (k(i), = 78 +/- 11 nM) and selectivity for IDE. Notably, the potency of these inhibitors was found to vary as much as 60-fold in a substrate-specific manner, an unexpected finding for active site-directed inhibitors. Collectively, our findings demonstrate that potent, small-molecule IDE inhibitors can be developed that, in certain instances, can be highly substrate selective.