(1S,4R)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3,6-dione | 640897-02-5

• 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,4R)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3,6-dione
• 英文别名: (1S,4R)-2-[(4-methoxyphenyl)methyl]-2-azabicyclo[2.2.1]heptane-3,6-dione
• CAS: 640897-02-5
• 化学式: C₁₄H₁₅NO₃
• 分子量: 245.278
• InChiKey: XDNGSLMBVIPJCH-PWSUYJOCSA-N

物化性质

• 沸点：
  471.3±45.0 °C(Predicted)
• 密度：
  1.280±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  18
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  46.6
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (1S,4R)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3,6-dione 在 盐酸 、 ammonium cerium(IV) nitrate 、 叔丁基锂 作用下， 以 四氢呋喃 、 乙腈 、 正戊烷 为溶剂， 反应 32.5h， 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：

  (1S,4R,6S)-6-hydroxy-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]-heptan-3-one 在 N-甲基吲哚酮 、 四丙基高钌酸铵 作用下， 以 二氯甲烷 为溶剂， 反应 24.0h， 以70%的产率得到(1S,4R)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3,6-dione
  参考文献：
  名称：

  Fluorinated Conformationally Restricted γ-Aminobutyric Acid Aminotransferase Inhibitors

  摘要：

  On the basis of the structures of several potent inhibitor molecules for gamma-aminobutryric acid aminotransferase (GABA-AT) that were previously reported, six modified fluorine-containing conformationally restricted analogues were designed, synthesized, and tested as GABA-AT inhibitors. The syntheses of all six molecules followed from a readily synthesized ketone intermediate. Three of the molecules were found to be irreversible inhibitors of GABA-AT with comparable or larger k(inact)/K-I values than that of vigabatrin, a clinically used antiepilepsy drug, and the other three were reversible inhibitors. A possible mechanism for inactivation by one of the inactivators is proposed.

  DOI：

  10.1021/jm0608715

文献信息

• Turnover and Inactivation Mechanisms for (<i>S</i>)-3-Amino-4,4-difluorocyclopent-1-enecarboxylic Acid, a Selective Mechanism-Based Inactivator of Human Ornithine Aminotransferase
  作者：Sida Shen、Arseniy Butrin、Peter F. Doubleday、Rafael D. Melani、Brett A. Beaupre、Mauricio T. Tavares、Glaucio M. Ferreira、Neil L. Kelleher、Graham R. Moran、Dali Liu、Richard B. Silverman

  DOI：10.1021/jacs.1c02456

  日期：2021.6.16

  (S)-3-amino-4,4-difluorocyclopent-1-enecarboxylic acid (SS-1-148, 6) was identified as a potent mechanism-based inactivator of hOAT while showing excellent selectivity over other related aminotransferases (e.g., GABA-AT). An integrated mechanistic study was performed to investigate the turnover and inactivation mechanisms of 6. A monofluorinated ketone (M10) was identified as the primary metabolite of 6 in hOAT

  抑制人鸟氨酸 δ-氨基转移酶 ( h OAT) 是治疗肝细胞癌的潜在治疗方法。在这项工作中，( S )-3-amino-4,4-difluorocyclopent-1-enecarboxylic acid (SS-1-148, 6 ) 被确定为一种有效的基于机制的h OAT灭活剂，同时显示出优于其他相关的选择性氨基转移酶（例如，GABA-AT）。进行了综合机理研究以研究6的周转和失活机制。单氟化酮 ( M10 ) 被确定为6 in h OAT 的主要代谢物。通过将h OAT 全酶晶体与如图6所示，成功捕获了M10的前体。这种与 Lys292 共价结合的宝石-二胺中间体首次在h OAT/配体晶体中观察到，验证了为6提出的周转机制。共结晶产生与6复合的h OAT，并揭示了 h 中一种新的非共价失活机制燕麦。天然蛋白质质谱法首次用于氨基转移酶灭活剂的研究，以验证配体和酶之间的非共价相互作用；共价
• Mechanism of Inactivation of Ornithine Aminotransferase by (1<i>S</i>,3<i>S</i>)-3-Amino-4-(hexafluoropropan-2-ylidenyl)cyclopentane-1-carboxylic Acid
  作者：Matthew J. Moschitto、Peter F. Doubleday、Daniel S. Catlin、Neil L. Kelleher、Dali Liu、Richard B. Silverman

  DOI：10.1021/jacs.9b03254

  日期：2019.7.10

  inactivates hOAT through fluoride ion elimination to an activated 1,1'-difluoroolefin, followed by conjugate addition and hydrolysis. This result was confirmed with additional studies, including the detection of the cofactor structure by mass spectrometry and through the identification of turnover metabolites. On the basis of this inactivation mechanism and to provide further evidence for the mechanism

  鸟氨酸转氨酶 (OAT) 是一种吡哆醛 5'-磷酸依赖性酶，它被认为可以治疗肝细胞癌 (HCC)，这是最常见的肝癌形式，目前还没有有效的治疗方法。从之前对我们的转氨酶抑制剂的评估中，发现 (1 S,3 S)-3-amino-4-(perfluoropropan-2-ylidene)cyclopentane-1-carboxy acid hydrochloride (1) 是一种选择性和有效的灭活剂人 OAT ( hOAT)，即使在 0.1 mg/kg 的剂量下，它也能抑制植入人源 HCC 的无胸腺小鼠的 HCC 生长。目前，正在进行研究性新药 (IND) 支持研究 1。然而，1 的失活机制已被证明是难以捉摸的。基于已知转氨酶失活剂的机制，我们在这里提出了三种可能的机制：迈克尔加成、烯胺加成和氟离子消除，然后是共轭加成。根据晶体学和完整蛋白质质谱法，确定 1 通过氟离子消除为活化的 1,1'
• 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。
• 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] (S)-3-AMINO-4,4-DIHALOCYCLOPENT-1-ENECARBOXYLIC ACID AS SELECTIVE INACTIVATORS OF HUMAN ORNITHINE AMINOTRANSFERASE<br/>[FR] ACIDE (S)-3-AMINO-4,4-DIHALOCYCLOPENT-1-CARBOXYLIQUE UTILISÉ EN TANT QU'INACTIVATEURS SÉLECTIFS DE L'ORNITHINE AMINOTRANSFÉRASE HUMAINE
  申请人：UNIV NORTHWESTERN

  公开号：WO2022187523A1

  公开（公告）日：2022-09-09

  Disclosed are amino, fluoro- substituted cyclopentene carboxylic acid compounds. The disclosed compounds and compositions thereof may be utilized in methods for modulating human ornithine δ-aminotransferase (hOAT) activity, including methods for treating diseases or disorders associated with tohOAT activity or expression such as cell proliferative diseases and disorders.

  本发明涉及氨基、氟取代的环戊烯羧酸化合物。所述化合物及其组成物可用于调节人鸟氨酸δ-氨基转移酶（hOAT）活性的方法，包括用于治疗与hOAT活性或表达相关的疾病或紊乱，例如细胞增殖性疾病和紊乱的方法。