CPP-115 | 640897-20-7

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: CPP-115
• 英文别名: (1S,3S)-3-amino-4-(difluoromethylenylidene)cyclopentane-1-carboxylic acid；(1S,3S)-3-amino-4-(difluoromethylidene)cyclopentane-1-carboxylic acid；(1S,3S)-3-amino-4-difluoromethylidene-1-cyclopentanoic acid；(1S,3S)-3-amino-4-difluoromethylene-1-cyclopentanoic acid；CPP-115 free base
• CAS: 640897-20-7
• 化学式: C₇H₉F₂NO₂
• 分子量: 177.151
• InChiKey: CBSRETZPFOBWNG-UCORVYFPSA-N

物化性质

• 沸点：
  269.6±40.0 °C(Predicted)
• 密度：
  1.380±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -2.7
• 重原子数：
  12
• 可旋转键数：
  1
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  63.3
• 氢给体数：
  2
• 氢受体数：
  5

制备方法与用途

CPP-115是一种口服的小分子药物，是新一代γ-氨基丁酸转氨酶（GABA-AT）抑制剂，其Ki值为31 μM，且没有其他γ-氨基丁酸能或旁路作用。

反应信息

• 作为反应物：
  描述：

  CPP-115 在 N-甲基吗啉 、 三乙胺 、 N,N-二异丙基乙胺 、 三氟乙酸酐 、 氯甲酸异丁酯 作用下， 以 四氢呋喃 、 甲苯 为溶剂， 反应 6.17h， 生成 (1S,4S)-3-difluoromethylene-4-phthalimidocyclopentanecarbonitrile
  参考文献：
  名称：

  Structural modifications of (1S,3S)-3-amino-4-difluoromethylenecyclopentanecarboxylic acid, a potent irreversible inhibitor of GABA aminotransferase

  摘要：

  Low brain levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) lead to convulsions. Inhibition of GABA aminotransferase increases the concentration of GABA and can terminate the convulsions. Earlier we reported the synthesis of (1S,3S)-3-amino-4-difluoromethylenecyclopentanecarboxylic acid (2), which is 186 times more potent an inactivator of GABA aminotransferase than the epilepsy drug S-vigabatrin. The corresponding dichloromethylene analogue of 2 (compound 3) has been made, but it shows only weak reversible inhibition of GABA aminotransferase. However, the tetrazole isostere of 2 (compound 4) has been found to be a time-dependent inactivator of GABA aminotransferase. Although it is 20 times less potent than carboxylic acid 2, it is 2.5 times more potent than S-vigabatrin. A calculation of the Clog P values indicates that 4 is the most lipophilic of the three, being 69 times more lipophilic than 2 and 55 times more lipophilic than S-vigabatrin, indicating potential for improved bioavailability. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2006.12.119
• 作为产物：
  描述：

  (1S,4S)-6-difluoromethylenyl-2-(4‘-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one 在 盐酸 作用下， 反应 10.0h， 以72%的产率得到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

文献信息

• [EN] FLUORINE SUBSTITUTED CECLOHEXENE ANALOGOUES OF GAMMA-AMINOBUTYRIC ACID (GABA)<br/>[FR] ANALOGUES DE CYCLOHEXÈNE SUBSTITUÉS PAR DU FLUOR DE L'ACIDE GAMMA-AMINOBUTYRIQUE (GABA)
  申请人：UNIV NORTHWESTERN

  公开号：WO2021081523A1

  公开（公告）日：2021-04-29

  Disclosed are amino, fluoro-sub stituted cyclohexene carboxylic acid compounds. The disclosed compounds and compositions thereof may be utilized in methods for modulating ornithine aminotransferase (OAT) activity, including methods for treating diseases or disorders associated with OAT activity or expression such as cell proliferative diseases and disorders.

  本文披露了氨基，氟代取代的环己烯羧酸化合物。所披露的化合物及其组合物可用于调节鸟氨酸氨基转移酶（OAT）活性的方法，包括用于治疗与OAT活性或表达相关的疾病或障碍的方法，如细胞增殖性疾病和障碍。
• Mechanism of Inactivation of γ-Aminobutyric Acid Aminotransferase by (1<i>S</i>,3<i>S</i>)-3-Amino-4-difluoromethylene-1-cyclopentanoic Acid (CPP-115)
  作者：Hyunbeom Lee、Emma H. Doud、Rui Wu、Ruslan Sanishvili、Jose I. Juncosa、Dali Liu、Neil L. Kelleher、Richard B. Silverman

  DOI：10.1021/ja512299n

  日期：2015.2.25

  brain, which can terminate seizures as well as have potential therapeutic applications in treating other neurological disorders, including drug addiction. Among the analogues that we previously developed, (1S,3S)-3-amino-4-difluoromethylene-1-cyclopentanoic acid (CPP-115) showed 187 times greater potency than that of vigabatrin, a known inactivator of GABA-AT and approved drug (Sabril) for the treatment

  γ-氨基丁酸氨基转移酶 (GABA-AT) 是一种 5'-磷酸吡哆醛 (PLP) 依赖性酶，可降解 GABA，GABA 是哺乳动物细胞中的主要抑制性神经递质。当 GABA 的浓度低于阈值水平时，可能会发生抽搐。抑制 GABA-AT 会提高大脑中的 GABA 水平，这可以终止癫痫发作，并且在治疗其他神经系统疾病（包括毒瘾）方面具有潜在的治疗应用。在我们之前开发的类似物中，(1S,3S)-3-amino-4-difluoromethylene-1-cyclopentanoic acid (CPP-115) 的效力比氨己烯酸（一种已知的 GABA-AT 灭活剂）强 187 倍，并已获批准用于治疗婴儿痉挛症和难治性成人癫痫的药物（Sabril）。最近，CPP-115 在 I 期临床试验中显示没有副作用。在这里，我们报告了 CPP-115 的新型灭活机制，这是一种基于机制的灭活剂，它经过 GABA-AT
• INACTIVATORS OF TOXOPLASMA GONDII ORNITHINE AMINOTRANSFERASE FOR TREATING TOXOPLASMOSIS AND MALARIA
  申请人：Northwestern University

  公开号：US20180098952A1

  公开（公告）日：2018-04-12

  Disclosed are methods, compounds, and compositions for treating infection by an Apicomplexan parasite that include administering a compound that selectively inactivates ornithine aminotransferase of the Apicomplexan parasite. Specifically, the methods, compounds, compounds may be utilized for treating infection by Toxoplasma gondii and toxoplasmosis and for treating infection by Plasmodium falciparum and malaria. The compounds disclosed herein are observed to selectively inactivate Toxoplasma gondii ornithine aminotransferase (TgOAT) relative to human OAT and relative to human γ-aminobutyric aminotransferase (GABA-AT).

  揭示了一种治疗具有选择性灭活裂殖孢子虫的鸟氨基转移酶的化合物、方法和组合物。具体来说，这些方法、化合物可用于治疗弓形虫和弓形虫病感染，以及治疗疟原虫和疟疾感染。本文披露的化合物被观察到相对于人类鸟氨基转移酶和人类γ-氨基丁酸氨基转移酶（GABA-AT）具有选择性地灭活弓形虫鸟氨基转移酶（TgOAT）。
• Use of (1S,3S)-3-amino-4-(difluoromethylidene) cyclopentane-1-carboxylic acid and (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid in the treatment of tinnitus, acute sensorineural hearing loss, meniere'S disease, tourette'S syndrome, attention deficit hyperactivity disorder and addiction
  申请人：Ovid Therapeutics Inc.

  公开号：US10653652B2

  公开（公告）日：2020-05-19

  Methods of treating tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette's syndrome, ADHD or addiction with (1S,3S)-3-amino-4-(difluoromethylidene) cyclopentane-1-carboxylic acid or a pharmaceutically acceptable salt thereof are provided. Methods of treating tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette's syndrome, ADHD or addiction with (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid are provided. Also provided are therapeutic compositions that may be used to improve one or more symptoms of tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette's syndrome, ADHD or addiction.

  提供了用(1S,3S)-3-氨基-4-(二氟亚基)环戊烷-1-羧酸或其药学上可接受的盐治疗耳鸣、急性感音神经性听力损失、美尼尔氏病、抽动秽语综合征、多动症或成瘾的方法。提供了用（S）-3-氨基-4-（二氟亚甲基）环戊-1-烯-1-羧酸治疗耳鸣、急性感音神经性听力损失、美尼尔氏病、抽动秽语综合征、多动症或成瘾的方法。还提供了可用于改善耳鸣、急性感音神经性听力损失、梅尼埃病、抽动秽语综合征、多动症或成瘾的一种或多种症状的治疗组合物。
• Inactivators of Toxoplasma gondii ornithine aminotransferase for treating toxoplasmosis and malaria
  申请人：Northwestern University

  公开号：US10632088B2

  公开（公告）日：2020-04-28

  Disclosed are methods, compounds, and compositions for treating infection by an Apicomplexan parasite that include administering a compound that selectively inactivates ornithine aminotransferase of the Apicomplexan parasite. Specifically, the methods, compounds, compounds may be utilized for treating infection by Toxoplasma gondii and toxoplasmosis and for treating infection by Plasmodium falciparum and malaria. The compounds disclosed herein are observed to selectively inactivate Toxoplasma gondii ornithine aminotransferase (TgOAT) relative to human OAT and relative to human γ-aminobutyric aminotransferase (GABA-AT).

  本发明公开了治疗弓形虫感染的方法、化合物和组合物，其中包括施用选择性灭活弓形虫鸟氨酸氨基转移酶的化合物。具体来说，这些方法、化合物可用于治疗弓形虫感染和弓形虫病，以及恶性疟原虫感染和疟疾。据观察，相对于人类鸟氨酸氨基转移酶（OAT）和人类γ-氨基丁酸氨基转移酶（GABA-AT），本文公开的化合物可选择性地灭活弓形虫鸟氨酸氨基转移酶（TgOAT）。