(3R,4R)-tert-butyl 3-((6-(benzyl(tert-butoxycarbonyl)amino)pyridin-2-yl)methyl)-4-(2-oxoethoxy)pyrrolidine-1-carboxylate | 1258299-31-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: (3R,4R)-tert-butyl 3-((6-(benzyl(tert-butoxycarbonyl)amino)pyridin-2-yl)methyl)-4-(2-oxoethoxy)pyrrolidine-1-carboxylate
• CAS: 1258299-31-8
• 化学式: C₂₉H₃₉N₃O₆
• 分子量: 525.645
• InChiKey: VTEUAODLXGWSOP-VWNXMTODSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.02
• 重原子数：
  38.0
• 可旋转键数：
  8.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  98.27
• 氢给体数：
  0.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  (3R,4R)-tert-butyl 3-((6-(benzyl(tert-butoxycarbonyl)amino)pyridin-2-yl)methyl)-4-(2-oxoethoxy)pyrrolidine-1-carboxylate 、 3-氟苯乙胺 在 三乙酰氧基硼氢化钠 作用下， 反应 2.0h， 以55%的产率得到(3R,4R)-tert-butyl 3-((6-(benzyl(tert-butoxycarbonyl)amino)pyridin-2-yl)methyl)-4-(2-(3-fluorophenethylamino)ethoxy)pyrrolidine-1-carboxylate
  参考文献：
  名称：

  Peripheral but crucial: A hydrophobic pocket (Tyr706, Leu337, and Met336) for potent and selective inhibition of neuronal nitric oxide synthase

  摘要：

  Selective inhibition of the neuronal isoform of nitric oxide synthase (nNOS) over endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) has become a promising strategy for the discovery of new therapeutic agents for neurodegenerative diseases. However, because of the high sequence homology of different isozymes in the substrate binding pocket, developing inhibitors with both potency and excellent isoform selectivity remains a challenging problem. Herein, we report the evaluation of a recently discovered peripheral hydrophobic pocket (Tyr(706), Leu(337), and Met(336)) that opens up upon inhibitor binding and its potential in designing potent and selective nNOS inhibitors using three compounds, 2a, 2b, and 3. Crystal structure results show that inhibitors 2a and 3 adopted the same binding mode as lead compound 1. We also found that hydrophobic interactions between the 4-methyl group of the aminopyridine ring of these compounds with the side chain of Met(336), as well as the π-π stacking interaction between the pyridinyl motif and the side chain of Tyr(706) are important for the high potency and selectivity of these nNOS inhibitors.

  DOI：

  10.1016/j.bmcl.2010.08.096
• 作为产物：
  描述：

  (3R,4R)-tert-butyl 3-(allyloxy)-4-((6-(benzyl(tert-butoxycarbonyl)amino)pyridin-2-yl)methyl)pyrrolidine-1-carboxylate 在 臭氧 、 溶剂黄146 、 锌 作用下， 以 二氯甲烷 为溶剂， 反应 1.5h， 以75%的产率得到(3R,4R)-tert-butyl 3-((6-(benzyl(tert-butoxycarbonyl)amino)pyridin-2-yl)methyl)-4-(2-oxoethoxy)pyrrolidine-1-carboxylate
  参考文献：
  名称：

  Peripheral but crucial: A hydrophobic pocket (Tyr706, Leu337, and Met336) for potent and selective inhibition of neuronal nitric oxide synthase

  摘要：

  Selective inhibition of the neuronal isoform of nitric oxide synthase (nNOS) over endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) has become a promising strategy for the discovery of new therapeutic agents for neurodegenerative diseases. However, because of the high sequence homology of different isozymes in the substrate binding pocket, developing inhibitors with both potency and excellent isoform selectivity remains a challenging problem. Herein, we report the evaluation of a recently discovered peripheral hydrophobic pocket (Tyr(706), Leu(337), and Met(336)) that opens up upon inhibitor binding and its potential in designing potent and selective nNOS inhibitors using three compounds, 2a, 2b, and 3. Crystal structure results show that inhibitors 2a and 3 adopted the same binding mode as lead compound 1. We also found that hydrophobic interactions between the 4-methyl group of the aminopyridine ring of these compounds with the side chain of Met(336), as well as the π-π stacking interaction between the pyridinyl motif and the side chain of Tyr(706) are important for the high potency and selectivity of these nNOS inhibitors.

  DOI：

  10.1016/j.bmcl.2010.08.096