(1S,4S)-6-difluoromethylenyl-2-(4‘-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one | 640897-07-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: (1S,4S)-6-difluoromethylenyl-2-(4‘-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one
• 英文别名: (1S,4S)-6-difluoromethenyl-2-(4'-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one；(1S,4S)-6-difluoromethylenyl-2-(4'-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one；(1S,4S)-6-(difluoromethylidene)-2-[(4-methoxyphenyl)methyl]-2-azabicyclo[2.2.1]heptan-3-one
• CAS: 640897-07-0
• 化学式: C₁₅H₁₅F₂NO₂
• 分子量: 279.286
• InChiKey: LZNIPMVPJZJGHK-GWCFXTLKSA-N

物化性质

• 沸点：
  418.2±45.0 °C(Predicted)
• 密度：
  1.299±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  20
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  29.5
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (1S,4S)-6-difluoromethylenyl-2-(4‘-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one 在 盐酸 、 ammonium cerium(IV) nitrate 作用下， 以 乙腈 为溶剂， 反应 14.0h， 生成 CPP-115
  参考文献：
  名称：

  Design, Synthesis, and Biological Activity of a Difluoro-Substituted, Conformationally Rigid Vigabatrin Analogue as a Potent γ-Aminobutyric Acid Aminotransferase Inhibitor

  摘要：

  Previously it was found that a conformationally rigid analogue (2) of the epilepsy drug vigabatrin (1) did not inactivate gamma-aminobutyric acid aminotransferase (GABA-AT), A cyclic compound with an exocyclic double bond (6) was synthesized and was found to inactivate GABA-AT, but only in the absence of 2-mereaptoethanol. The corresponding difluoro-substituted analogue (14) was synthesized and was shown to be a very potent time-dependent inhibitor, even in the presence of 2-mercaptoethanol.

  DOI：

  10.1021/jm034162s
• 作为产物：
  描述：

  二氟甲基膦酸二乙酯 、 (1S,4R)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3,6-dione 在 叔丁基锂 作用下， 以 四氢呋喃 、 正戊烷 为溶剂， 反应 25.5h， 以68%的产率得到(1S,4S)-6-difluoromethylenyl-2-(4‘-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one
  参考文献：
  名称：

  Compounds and related methods for inhibition of &ggr;-aminobutyric acid aminotransferase

  摘要：

  (1S, 3S)-3-氨基-4-二氟甲基-1-环戊氨酸展示了一类新型化合物，作为&ggr;-氨基丁酸氨基转移酶（GABA-AT）的有效不可逆抑制剂。相应的单氟取代化合物也是GABA-AT的有效时间依赖性抑制剂。

  公开号：

  US06794413B1

文献信息

• Rational Design, Synthesis, and Mechanism of (3<i>S</i>,4<i>R</i>)-3-Amino-4-(difluoromethyl)cyclopent-1-ene-1-carboxylic Acid: Employing a Second-Deprotonation Strategy for Selectivity of Human Ornithine Aminotransferase over GABA Aminotransferase
  作者：Wei Zhu、Arseniy Butrin、Rafael D. Melani、Peter F. Doubleday、Glaucio Monteiro Ferreira、Mauricio T. Tavares、Thahani S. Habeeb Mohammad、Brett A. Beaupre、Neil L. Kelleher、Graham R. Moran、Dali Liu、Richard B. Silverman

  DOI：10.1021/jacs.2c00924

  日期：2022.3.30

  Human ornithine aminotransferase (hOAT) is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that contains a similar active site to that of γ-aminobutyric acid aminotransferase (GABA-AT). Recently, pharmacological inhibition of hOAT was recognized as a potential therapeutic approach for hepatocellular carcinoma. In this work, we first studied the inactivation mechanisms of hOAT by two well-known GABA-AT

  人鸟氨酸转氨酶 (hOAT) 是一种 5'-磷酸吡哆醛 (PLP) 依赖性酶，其活性位点与 γ-氨基丁酸转氨酶 (GABA-AT) 相似。最近，hOAT 的药理学抑制被认为是肝细胞癌的潜在治疗方法。在这项工作中，我们首先研究了两种著名的 GABA-AT 灭活剂（CPP-115和OV329）对 hOAT 的灭活机制。受这两种氨基转移酶灭活机制差异的启发，设计并合成了一系列类似物，从而发现了类似物10b作为一种高选择性和有效的 hOAT 抑制剂。完整的蛋白质质谱、蛋白质晶体学和透析实验表明，10b在 hOAT 的活性位点转化为不可逆的紧密结合加合物 ( 34 )，不饱和类似物 ( 11 )也是如此。10b和11之间的动力学研究比较表明，活性中间体 ( 17b ) 仅在 hOAT 中产生，而不在 GABA-AT 中产生。分子对接研究和 p Ka计算计算突出了手性和环内双键对抑制活性的重要性。10
• [EN] ORNITHINE AMINOTRANSFERASE INHIBITION WITH GABA ANALOGUES FOR TREATMENT OF HEPATOCELLULAR CARCINOMA<br/>[FR] INHIBITION DE L'ORNITHINE AMINOTRANSFÉRASE AVEC DES ANALOGUES DU GABA POUR LE TRAITEMENT DU CARCINOME HÉPATOCELLULAIRE
  申请人：UNIV NORTHWESTERN

  公开号：WO2016073983A3

  公开（公告）日：2016-08-11
• Design, Synthesis, and Biological Activity of a Difluoro-Substituted, Conformationally Rigid Vigabatrin Analogue as a Potent γ-Aminobutyric Acid Aminotransferase Inhibitor
  作者：Yue Pan、Jian Qiu、Richard B. Silverman

  DOI：10.1021/jm034162s

  日期：2003.12.1

  Previously it was found that a conformationally rigid analogue (2) of the epilepsy drug vigabatrin (1) did not inactivate gamma-aminobutyric acid aminotransferase (GABA-AT), A cyclic compound with an exocyclic double bond (6) was synthesized and was found to inactivate GABA-AT, but only in the absence of 2-mereaptoethanol. The corresponding difluoro-substituted analogue (14) was synthesized and was shown to be a very potent time-dependent inhibitor, even in the presence of 2-mercaptoethanol.
• Compounds and related methods for inhibition of &ggr;-aminobutyric acid aminotransferase
  申请人：Northwestern University

  公开号：US06794413B1

  公开（公告）日：2004-09-21

  (1S, 3S)-3-Amino-4-difluoromethylene-1-cyclopentanoic acid illustrates a novel class of compounds as potent irreversible inhibitors of &ggr;-aminobutyric acid aminotransferase (GABA-AT). The corresponding monofluoro-substituted compounds also are potent time-dependent inhibitors of GABA-AT.

  (1S, 3S)-3-氨基-4-二氟甲基-1-环戊氨酸展示了一类新型化合物，作为&ggr;-氨基丁酸氨基转移酶（GABA-AT）的有效不可逆抑制剂。相应的单氟取代化合物也是GABA-AT的有效时间依赖性抑制剂。