tert-butyl (3S,4R)-3-[6-(benzyl-tert-butoxycarbonyl-amino)-4-methyl-pyridin-2-ylmethyl]-4-{2-[2-(3-fluoro-phenyl)-ethylamino]-ethoxy}-pyrrolidine-1-carboxylate | 1018910-21-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: tert-butyl (3S,4R)-3-[6-(benzyl-tert-butoxycarbonyl-amino)-4-methyl-pyridin-2-ylmethyl]-4-{2-[2-(3-fluoro-phenyl)-ethylamino]-ethoxy}-pyrrolidine-1-carboxylate
• 英文别名: tert-butyl (3S,4R)-3-[[6-[benzyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]-4-methylpyridin-2-yl]methyl]-4-[2-[2-(3-fluorophenyl)ethylamino]ethoxy]pyrrolidine-1-carboxylate
• CAS: 1018910-21-8
• 化学式: C₃₈H₅₁FN₄O₅
• 分子量: 662.845
• InChiKey: FVDDHHXPIAZNFF-DITALETJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.5
• 重原子数：
  48
• 可旋转键数：
  16
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  93.2
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  tert-butyl (3S,4R)-3-[6-(benzyl-tert-butoxycarbonyl-amino)-4-methyl-pyridin-2-ylmethyl]-4-{2-[2-(3-fluoro-phenyl)-ethylamino]-ethoxy}-pyrrolidine-1-carboxylate 、 二碳酸二叔丁酯 在 sodium hydroxide 作用下， 以 二氯甲烷 为溶剂， 反应 24.0h， 以62%的产率得到tert-butyl (3S,4R)-3-[6-(benzyl-tert-butoxycarbonyl-amino)-4-methyl-pyridin-2-ylmethyl]-4-(2-{tert-butoxycarbonyl-[2-(3-fluoro-phenyl)-ethyl]-amino}-ethoxy)-pyrrolidine-1-carboxylate
  参考文献：
  名称：

  Exploration of the Active Site of Neuronal Nitric Oxide Synthase by the Design and Synthesis of Pyrrolidinomethyl 2-Aminopyridine Derivatives

  摘要：

  Neuronal nitric oxide synthase (nNOS) represents an important therapeutic target for the prevention of brain injury and the treatment of various neurodegenerative disorders. A series of trans-substituted amino pyrrolidinomethyl 2-aminopyridine derivatives (8-34) was designed and synthesized. A structure activity relationship analysis led to the discovery of low nanomolar nNOS inhibitors ((+/-)-32 and (+/-)-34) with more than 1000-fold selectivity for nNOS over eNOS. Four enantiomerically pure isomers of 3'-[2 ''-(3 ''-fluorophenethylamino)ethoxy]pyrrolidin-4'-yl}methyl}-4-methylpyridin-2-amine (4) also were synthesized. It was found that (3'R,4'R)-4 can induce enzyme elasticity to generate a new "hot spot" for ligand binding. The inhibitor adopts a unique binding mode, the same as that observed for (3'R,4'R)-3'-[2 ''-(3'''-fluorophenethylamino)ethylamino]pyrrolidin-4'-yl}methyl}-4-methylpyridin-2-amine ((3'R,4'R)-3) (J. Am. Chem. Soc. 2010, 132 (15), 5437-5442). On the basis of structure-activity relationships of 8-34 and different binding conformations of the cis and trans isomers of 3 and 4, critical structural requirements of the NOS active site for ligand binding are revealed.

  DOI：

  10.1021/jm100947x
• 作为产物：
  描述：

  tert-butyl (3S,4R)-3-[6-(benzyl-tert-butoxycarbonyl-amino)-4-methyl-pyridin-2-ylmethyl]-4-(2-oxo-ethoxy)-pyrrolidine-1-carboxylate 、 3-氟苯乙胺 在 三乙酰氧基硼氢化钠 作用下， 以 1,2-二氯乙烷 为溶剂， 反应 14.0h， 以77%的产率得到tert-butyl (3S,4R)-3-[6-(benzyl-tert-butoxycarbonyl-amino)-4-methyl-pyridin-2-ylmethyl]-4-{2-[2-(3-fluoro-phenyl)-ethylamino]-ethoxy}-pyrrolidine-1-carboxylate
  参考文献：
  名称：

  Exploration of the Active Site of Neuronal Nitric Oxide Synthase by the Design and Synthesis of Pyrrolidinomethyl 2-Aminopyridine Derivatives

  摘要：

  Neuronal nitric oxide synthase (nNOS) represents an important therapeutic target for the prevention of brain injury and the treatment of various neurodegenerative disorders. A series of trans-substituted amino pyrrolidinomethyl 2-aminopyridine derivatives (8-34) was designed and synthesized. A structure activity relationship analysis led to the discovery of low nanomolar nNOS inhibitors ((+/-)-32 and (+/-)-34) with more than 1000-fold selectivity for nNOS over eNOS. Four enantiomerically pure isomers of 3'-[2 ''-(3 ''-fluorophenethylamino)ethoxy]pyrrolidin-4'-yl}methyl}-4-methylpyridin-2-amine (4) also were synthesized. It was found that (3'R,4'R)-4 can induce enzyme elasticity to generate a new "hot spot" for ligand binding. The inhibitor adopts a unique binding mode, the same as that observed for (3'R,4'R)-3'-[2 ''-(3'''-fluorophenethylamino)ethylamino]pyrrolidin-4'-yl}methyl}-4-methylpyridin-2-amine ((3'R,4'R)-3) (J. Am. Chem. Soc. 2010, 132 (15), 5437-5442). On the basis of structure-activity relationships of 8-34 and different binding conformations of the cis and trans isomers of 3 and 4, critical structural requirements of the NOS active site for ligand binding are revealed.

  DOI：

  10.1021/jm100947x

文献信息

• Potent and highly selective heteroaromatic inhibitors of neuronal nitric oxide synthase
  申请人：Silverman B. Richard

  公开号：US20080108814A1

  公开（公告）日：2008-05-08

  Peptidomimetic compounds as can inhibit neuronal nitric oxide synthase (nNOS) for potential treatment in neurodegenerative diseases, such as but not limited to stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease.

  肽类类似物化合物可抑制神经元一氧化氮合酶(nNOS)，用于潜在的治疗神经退行性疾病，如中风、阿尔茨海默病、帕金森病、亨廷顿病等。
• US7994326B2
  申请人：——

  公开号：US7994326B2

  公开（公告）日：2011-08-09
• [EN] POTENT AND HIGHLY SELECTIVE HETEROAROMATIC INHIBITORS OF NEURONAL NITRIC OXIDE SYNTHASE<br/>[FR] INHIBITEURS HÉTÉROAROMATIQUES PUISSANTS ET HAUTEMENT SÉLECTIFS DE LA MONOXYDE D'AZOTE SYNTHASE NEURONALE
  申请人：UNIV NORTHWESTERN

  公开号：WO2008042353A1

  公开（公告）日：2008-04-10

  [EN] Peptidomimetic compounds as can inhibit neuronal nitric oxide synthase (nNOS) for potential treatment in neurodegenerative diseases, such as but not limited to stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease.
  [FR] L'invention concerne des composés peptidomimétiques capables d'inhiber la monoxyde d'azote synthase neuronale (nNOS) dans le traitement potentiel de maladies neurodégénératives, telles que, mais sans en exclure d'autres, l'accident vasculaire cérébral, la maladie d'Alzheimer, la maladie de Parkinson et la maladie de Huntington.
• Exploration of the Active Site of Neuronal Nitric Oxide Synthase by the Design and Synthesis of Pyrrolidinomethyl 2-Aminopyridine Derivatives
  作者：Haitao Ji、Silvia L. Delker、Huiying Li、Pavel Martásek、Linda J. Roman、Thomas L. Poulos、Richard B. Silverman

  DOI：10.1021/jm100947x

  日期：2010.11.11

  Neuronal nitric oxide synthase (nNOS) represents an important therapeutic target for the prevention of brain injury and the treatment of various neurodegenerative disorders. A series of trans-substituted amino pyrrolidinomethyl 2-aminopyridine derivatives (8-34) was designed and synthesized. A structure activity relationship analysis led to the discovery of low nanomolar nNOS inhibitors ((+/-)-32 and (+/-)-34) with more than 1000-fold selectivity for nNOS over eNOS. Four enantiomerically pure isomers of 3'-[2 ''-(3 ''-fluorophenethylamino)ethoxy]pyrrolidin-4'-yl}methyl}-4-methylpyridin-2-amine (4) also were synthesized. It was found that (3'R,4'R)-4 can induce enzyme elasticity to generate a new "hot spot" for ligand binding. The inhibitor adopts a unique binding mode, the same as that observed for (3'R,4'R)-3'-[2 ''-(3'''-fluorophenethylamino)ethylamino]pyrrolidin-4'-yl}methyl}-4-methylpyridin-2-amine ((3'R,4'R)-3) (J. Am. Chem. Soc. 2010, 132 (15), 5437-5442). On the basis of structure-activity relationships of 8-34 and different binding conformations of the cis and trans isomers of 3 and 4, critical structural requirements of the NOS active site for ligand binding are revealed.