(2S)-amino-1-[[(1,1'-biphenyl)-4-yl]methyl]hexahydro-2H-azepin-2-one | 361385-60-6

• 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: (2S)-amino-1-[[(1,1'-biphenyl)-4-yl]methyl]hexahydro-2H-azepin-2-one
• 英文别名: (3S)-amino-1-[[(1,1'-biphenyl)-4-yl]methyl]hexahydro-2H-azepin-2-one；(3S)-3-amino-1-[(4-phenylphenyl)methyl]azepan-2-one
• CAS: 361385-60-6
• 化学式: C₁₉H₂₂N₂O
• 分子量: 294.396
• InChiKey: GZVVTNWMMAQHOY-SFHVURJKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  46.3
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (2S)-amino-1-[[(1,1'-biphenyl)-4-yl]methyl]hexahydro-2H-azepin-2-one 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 生成 [4-[(R)-2-Amino-2-((S)-1-biphenyl-4-ylmethyl-2-oxo-azepan-3-ylcarbamoyl)-ethyl]-2-(diethoxy-phosphoryl)-phenyl]-phosphonic acid diethyl ester
  参考文献：
  名称：

  Requirements for Specific Binding of Low Affinity Inhibitor Fragments to the SH2 Domain of ^pp60Src Are Identical to Those for High Affinity Binding of Full Length Inhibitors

  摘要：

  Results from a novel approach which uses protein crystallography for the screening of a low affinity inhibitor fragment library are analyzed by comparing the X-ray structures with bound fragments to the structures with the corresponding full length inhibitors. The screen for new phospho-tyrosine mimics binding to the SH2 domain of (pp60)src was initiated because of the limited cell penetration of phosphates. Fragments in our library typically had between 6 and 30 atoms and included compounds which had either millimolar activity in a Biacore assay or were suggested by the ab initio design program LUDI but had no measurable affinity. All identified fragments were located in the phospho-tyrosine pocket. The most promising fragments were successfully used to replace the phospho-tyrosine and resulted in novel nonpeptidic high affinity inhibitors. The significant diversity of successful fragments is reflected in the high flexibility of the phospho-tyrosine pocket. Comparison of the X-ray structures shows that the presence of the H-bond acceptors and not their relative position within the pharmacophore are essential for fragment binding and/or high affinity binding of full length inhibitors. The X-ray data show that the fragments are recognized by forming a complex H-bond network within the phospho-tyrosine pocket of SH2. No fragment structure was found in which this H-bond network was incomplete, and any uncompensated H-bond within the H-bond network leads to a significant decrease in the affinity of full length inhibitors. No correlation between affinity and fragment binding was found for these polar fragments and hence affinity-based screening would have overlooked some interesting starting points for inhibitor design. In contrast, we were unable to identify electron density for hydrophobic fragments, confirming that hydrophobic interactions are important for inhibitor affinity but of minor importance for ligand recognition. Our results suggest that a screening approach using protein crystallography is particularly useful to identify universal fragments for the conserved hydrophilic recognition sites found in target families such as SH2 domains, phosphatases, kinases, proteases, and esterases.

  DOI：

  10.1021/jm020970s
• 作为产物：
  描述：

  4-溴甲基联苯 在 氢氧化钾 、 四丁基碘化铵 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 2.0h， 生成 (2S)-amino-1-[[(1,1'-biphenyl)-4-yl]methyl]hexahydro-2H-azepin-2-one
  参考文献：
  名称：

  Discovery of highly potent Src SH2 binders: Structure–activity studies and X-ray structures

  摘要：

  Optimization of the hydrophobic moiety of caprolactam/thiazepinone based compounds led to the identification of potent Src SH2 binders in two different series incorporating a phosphotyrosine group (RU 81843) or a phosphobenzoic group (RU 79181). The X-ray co-structures with the Src SH2 domain revealed different binding modes for RU 81843 and RU 79181, and an excellent fit between RU81843 and the Src SH2 protein thus explaining its high potency (9 nM, 15-fold more potent than pYEE1 reference peptide). (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(02)00139-7

文献信息

• 2-ALKOXY-3,4,5-TRIHYDROXY-ALKYLAMIDES, PREPARATION THEREOF, COMPOSITIONS CONTAINING THEM AND USE THEREOF
  申请人：ZHANG Jidong

  公开号：US20070244087A1

  公开（公告）日：2007-10-18

  The invention relates particularly to 2-alkoxy-3,4,5-trihydroxy-alkylamides, preparation thereof, compositions containing them and use thereof as a medicament, particularly as anti-cancer agents.

  该发明特别涉及2-烷氧基-3,4,5-三羟基-烷酰胺，其制备方法，含有它们的组合物以及将其用作药物，特别是作为抗癌剂的用途。
• SAR and X-ray. A New Approach Combining Fragment-Based Screening and Rational Drug Design:  Application to the Discovery of Nanomolar Inhibitors of Src SH2
  作者：Dominique Lesuisse、Gudrun Lange、Pierre Deprez、Didier Bénard、Bernard Schoot、Georges Delettre、Jean-Pierre Marquette、Pierre Broto、Véronique Jean-Baptiste、Paulette Bichet、Edoardo Sarubbi、Eliane Mandine

  DOI：10.1021/jm010927p

  日期：2002.6.1

  ligands for Src SH2, we looked for phosphate replacements. For this, we have designed an SAR by fragment crystallography approach. The start of this work resulted from two experimental observations. First, the fact that phenyl phosphate itself displayed detectable binding affinity for Src SH2 permitted us to perform a screening of small aromatic compounds as phenyl phosphate surrogates. Second, the obtention

  （pp60）Src是一种参与信号转导的蛋白质，主要在神经元，血小板和破骨细胞中表达。最近在Soriano的KO实验中发现了其确切的生物学作用，除了骨质疏松症外没有其他明显的表型，这种疾病导致骨形成过多。Src家族的SH2结构域特异性识别在+1和+3位置具有磷酸酪氨酸和亲脂氨基酸特征的四肽序列。最近，我们通过该四肽的模块化肽模拟来寻找SH2配体。这产生了数个纳摩尔抑制剂家族。最好的是结合己内酰胺支架，联苯部分和磷酸酪氨酸。但是，这些抑制剂仍然结合了磷酸基团，赋予了与蛋白质良好的结合亲和力。磷酸盐对于候选药物具有不良的特征，即磷酸酶使磷酸基团的高水解速率和高电荷含量阻止了细胞渗透。因此，在寻找Src SH2的最佳非肽配体时，我们寻找了磷酸盐替代物。为此，我们通过碎片晶体学方法设计了SAR。这项工作的开始源于两个实验观察。首先，磷酸苯酯本身对Src SH2表现出可检测的结合亲和力，这一事实使我们
• 2-ALCOXY-3,4,5-TRIHYDROXY-ALKYLAMIDES, LEUR PREPARATION, COMPOSITIONS LES CONTENANT ET UTILISATION
  申请人：Aventis Pharma S.A.

  公开号：EP1819679A2

  公开（公告）日：2007-08-22
• US7550453B2
  申请人：——

  公开号：US7550453B2

  公开（公告）日：2009-06-23
• [EN] CAPROLACTAM DERIVATIVES AND USES THEREOF<br/>[FR] DERIVES DE CAPROLACTAM ET LEURS UTILISATIONS
  申请人：ARIAD PHARMA INC

  公开号：WO2001068655A2

  公开（公告）日：2001-09-20

  The invention involves derivatives of caprolactam of the formula (I) in which [A?1], A2 and R1¿ have the meanings indicated in the description, their salts and their prodrugs. The invention also relates to the preparation of such compounds, synthetic intermediates, their use, and in particular, antagonists of the Src SH2 domain and inhibitors of bone resorption and pharmaceutical compounds containing such compounds.