(3'S,4'R)-tert-butyl 3'-acetoxy-4'-{{6''-[benzyl(tert-butoxycarbonyl)amino]-4''-methylpyridin-2''-yl}methyl}pyrrolidine-1'-carboxylate | 1018909-86-8

• 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: (3'S,4'R)-tert-butyl 3'-acetoxy-4'-{{6''-[benzyl(tert-butoxycarbonyl)amino]-4''-methylpyridin-2''-yl}methyl}pyrrolidine-1'-carboxylate
• 英文别名: tert-butyl (3S,4R)-3-acetoxy-4-[6-(benzyl-tert-butoxycarbonyl-amino)-4-methyl-pyridin-2-ylmethyl]-pyrrolidine-1-carboxylate；tert-butyl (3S,4R)-3-acetyloxy-4-[[6-[benzyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]-4-methylpyridin-2-yl]methyl]pyrrolidine-1-carboxylate
• CAS: 1018909-86-8
• 化学式: C₃₀H₄₁N₃O₆
• 分子量: 539.672
• InChiKey: SNOHRTVWQOPHBY-ILBGXUMGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  39
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  98.3
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (3'S,4'R)-tert-butyl 3'-acetoxy-4'-{{6''-[benzyl(tert-butoxycarbonyl)amino]-4''-methylpyridin-2''-yl}methyl}pyrrolidine-1'-carboxylate 在 sodium carbonate 作用下， 以 甲醇 、 水 为溶剂， 反应 14.0h， 以100%的产率得到(+/-)-tert-butyl 3-((6'-[benzyl(tert-butoxycarbonyl)amino]-4'-methylpyridin-2'-yl)methyl)-4-hydroxypyrrolidine-1-carboxylate
  参考文献：
  名称：

  Unexpected Binding Modes of Nitric Oxide Synthase Inhibitors Effective in the Prevention of a Cerebral Palsy Phenotype in an Animal Model

  摘要：

  Selective inhibition of the neuronal isoform of nitric oxide synthase NOS (nNOS) has been shown to prevent brain injury and is important for the treatment of various neurodegenerative disorders. However, given the high active site conservation among all three NOS isoforms, the design of selective inhibitors is an extremely challenging problem. Here we present the structural basis for why novel and potent nNOS inhibitors exhibit the highest level of selectivity over eNOS reported so far (similar to 3,800-fold). By using a combination of crystallography, computational methods, and site-directed mutagenesis, we found that inhibitor chirality and an unanticipated structural change of the target enzyme control both the orientation and selectivity of these novel nNOS inhibitors. A new hot spot generated as a result of enzyme elasticity provides important information for the future fragment-based design of selective NOS inhibitors.

  DOI：

  10.1021/ja910228a
• 作为产物：
  描述：

  (3'R,4'R)-tert-butyl 3'-{{6''-[benzyl(tert-butoxycarbonyl)-amino]-4''-methylpyridin-2''-yl}methyl}-4'-hydroxypyrrolidine-1'carboxylate 、 溶剂黄146 在 偶氮二甲酸二异丙酯 、 三苯基膦 作用下， 以 四氢呋喃 为溶剂， 反应 48.0h， 以74%的产率得到(3'S,4'R)-tert-butyl 3'-acetoxy-4'-{{6''-[benzyl(tert-butoxycarbonyl)amino]-4''-methylpyridin-2''-yl}methyl}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。
• Selective Neuronal Nitric Oxide Synthase Inhibitors
  申请人：Silverman Richard B.

  公开号：US20120258513A1

  公开（公告）日：2012-10-11

  Compounds and related methods for selective inhibition of neuronal nitric oxide synthase over inducible and endothelial isoforms, such compounds as can provide reduced cationic character and enhanced bioavailability.
• US7994326B2
  申请人：——

  公开号：US7994326B2

  公开（公告）日：2011-08-09
• US8557552B2
  申请人：——

  公开号：US8557552B2

  公开（公告）日：2013-10-15
• [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.