N(1)-[(3'S,4'S)-4'-((6''-amino-4''-methylpyridin-2''-yl)methyl)pyrrolidin-3'-yl]-N(2)-(3'-fluorophenethyl)ethane-1,2-diamine tetrahydrochloride

• 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: N(1)-[(3'S,4'S)-4'-((6''-amino-4''-methylpyridin-2''-yl)methyl)pyrrolidin-3'-yl]-N(2)-(3'-fluorophenethyl)ethane-1,2-diamine tetrahydrochloride
• 英文别名: N-[(3R,4S)-4-(6-amino-4-methyl-pyridin-2-ylmethyl)-pyrrolidin-3-yl]-N'-[2-(3-fluoro-phenyl)-ethyl]-ethane-1,2-diamine tetrahydrochloride；N'-[(3R,4S)-4-[(6-amino-4-methylpyridin-2-yl)methyl]pyrrolidin-3-yl]-N-[2-(3-fluorophenyl)ethyl]ethane-1,2-diamine;hydrochloride
• 化学式: C₂₁H₃₀FN₅*4ClH
• 分子量: 517.345
• InChiKey: VMKLHBDAKACSJD-ZHXLSBKVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.09
• 重原子数：
  28
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  75
• 氢给体数：
  5
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  3-氟苯乙醛 在 palladium 10% on activated carbon 盐酸 、 氢气 、 三乙酰氧基硼氢化钠 、 戴斯-马丁氧化剂 、 sodium hydroxide 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 1,2-二氯乙烷 为溶剂， 生成 N(1)-[(3'S,4'S)-4'-((6''-amino-4''-methylpyridin-2''-yl)methyl)pyrrolidin-3'-yl]-N(2)-(3'-fluorophenethyl)ethane-1,2-diamine tetrahydrochloride
  参考文献：
  名称：

  [EN] SPECIFIC NNOS INHIBITORS FOR THE THERAPY AND PREVENTION OF HUMAN MELANOMA
  [FR] INHIBITEURS DE NNOS SPÉCIFIQUES POUR LA THÉRAPIE ET LA PRÉVENTION DU MÉLANOME HUMAIN

  摘要：

  公开号：

  WO2012097121A9

文献信息

• Discovery of Highly Potent and Selective Inhibitors of Neuronal Nitric Oxide Synthase by Fragment Hopping
  作者：Haitao Ji、Huiying Li、Pavel Martásek、Linda J. Roman、Thomas L. Poulos、Richard B. Silverman

  DOI：10.1021/jm801220a

  日期：2009.2.12

  appropriate lipophilic fragments for lead optimization. More potent and selective inhibitors with better druglike properties were obtained within the design of 20 derivatives (compounds 7−26). Our structure-based inhibitor design for nNOS and SAR analysis reveal the robustness and efficiency of fragment hopping in lead discovery and structural optimization, which implicates a broad application of this

  选择性抑制神经元一氧化氮合酶 (nNOS) 已被证明可以预防脑损伤，并且对于治疗各种神经退行性疾病很重要。该研究表明，通过片段跳跃不仅可以获得更高的抑制效力和同工酶选择性，而且可以获得更多的药物特性。基于先导分子6的结构，片段跳跃有效地提取了 nNOS 活性位点中最少的药效成分，用于配体疏水和空间相互作用，并生成合适的亲脂性片段用于先导优化。在 20 种衍生物（化合物7 - 26）。我们用于 nNOS 和 SAR 分析的基于结构的抑制剂设计揭示了片段跳跃在先导发现和结构优化中的稳健性和效率，这意味着这种方法可以广泛应用于许多其他治疗靶点，而这些治疗靶点已知的药物样小分子调节剂仍然有限.
• 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.
• Unexpected Binding Modes of Nitric Oxide Synthase Inhibitors Effective in the Prevention of a Cerebral Palsy Phenotype in an Animal Model
  作者：Silvia L Delker、Haitao Ji、Huiying Li、Joumana Jamal、Jianguo Fang、Fengtian Xue、Richard B. Silverman、Thomas L. Poulos

  DOI：10.1021/ja910228a

  日期：2010.4.21

  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.
• [EN] SPECIFIC NNOS INHIBITORS FOR THE THERAPY AND PREVENTION OF HUMAN MELANOMA<br/>[FR] INHIBITEURS DE NNOS SPÉCIFIQUES POUR LA THÉRAPIE ET LA PRÉVENTION DU MÉLANOME HUMAIN
  申请人：UNIV NORTHWESTERN

  公开号：WO2012097121A9

  公开（公告）日：2012-10-04