2-(4-(2-(三氟甲基)苯基)哌啶-1-甲酰胺基)苯甲酸 | 1152782-19-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 中文名称: 2-(4-(2-(三氟甲基)苯基)哌啶-1-甲酰胺基)苯甲酸
• 英文名称: 2-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carboxamido)benzoic acid
• 英文别名: A1120；2-[[4-[2-(trifluoromethyl)phenyl]piperidine-1-carbonyl]amino]benzoic acid
• CAS: 1152782-19-8
• 化学式: C₂₀H₁₉F₃N₂O₃
• 分子量: 392.378
• InChiKey: MEAQCLPMSVEOQF-UHFFFAOYSA-N

物化性质

• 沸点：
  572.3±50.0 °C(Predicted)
• 密度：
  1.370±0.06 g/cm3(Predicted)
• 溶解度：
  二甲基亚砜：100 mM；乙醇：25 mM

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  28
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  69.6
• 氢给体数：
  2
• 氢受体数：
  6

安全信息

• 危险类别：
  9
• 危险性防范说明：
  P501,P273,P260,P270,P264,P280,P391,P314,P337+P313,P305+P351+P338,P301+P312+P330
• 危险品运输编号：
  3077
• 危险性描述：
  H302,H319,H372,H410
• 包装等级：
  III

制备方法与用途

生物活性

A 1120 是一种高亲和力的视黄醇结合蛋白 4 (RBP4) 的拮抗剂，其 Ki 值为 8.3 nM。A 1120 能够破坏 RBP4 与其结合体转甲状腺素之间的相互作用。

靶点

• Ki: 8.3 nM (视黄醇结合蛋白 4)

体外研究

• A 1120 在人类和小鼠 RBP4 上的 IC₅₀ 分别为 90 nM 和 66 nM。

反应信息

• 作为反应物：
  描述：

  2-(4-(2-(三氟甲基)苯基)哌啶-1-甲酰胺基)苯甲酸 在 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 1.5h， 以83%的产率得到7-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-azabicyclo[4.2.0]-octa-1(6),2,4-trien-8-one
  参考文献：
  名称：

  Design, Synthesis, and Evaluation of Nonretinoid Retinol Binding Protein 4 Antagonists for the Potential Treatment of Atrophic Age-Related Macular Degeneration and Stargardt Disease

  摘要：

  Accumulation of lipofuscin in the retina is associated with pathogenesis of atrophic age-related macular degeneration and Stargardt disease. Lipofuscin bisretinoids (exemplified by N-retinylidene-N-retinylethanolamine) seem to mediate lipofuscin toxicity. Synthesis of lipofuscin bisretinoids depends on the influx of retinol from serum to the retina. Compounds antagonizing the retinol-dependent interaction of retinol-binding protein 4 (RBP4) with transthyretin in the serum would reduce serum RBP4 and retinol and inhibit bisretinoid formation. We recently showed that A1120 (3), a potent carboxylic acid based RBP4 antagonist, can significantly reduce lipofuscin bisretinoid formation in the retinas of Abca4(-/-). mice. As part of the NIH Blueprint Neurotherapeutics Network project we undertook the in vitro exploration to identify novel conformationally flexible and constrained RBP4 antagonists with improved potency and metabolic stability. We also demonstrate that upon acute and chronic dosing in rats, 43, a potent cyclopentyl fused pyrrolidine antagonist, reduced circulating plasma RBP4 protein levels by approximately 60%.

  DOI：

  10.1021/jm5010013
• 作为产物：
  描述：

  邻溴三氟甲苯 在 正丁基锂 、 氯化亚砜 、 palladium 10% on activated carbon 、 甲酸铵 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 为溶剂， 反应 11.08h， 生成 2-(4-(2-(三氟甲基)苯基)哌啶-1-甲酰胺基)苯甲酸
  参考文献：
  名称：

  Design, Synthesis, and Evaluation of Nonretinoid Retinol Binding Protein 4 Antagonists for the Potential Treatment of Atrophic Age-Related Macular Degeneration and Stargardt Disease

  摘要：

  Accumulation of lipofuscin in the retina is associated with pathogenesis of atrophic age-related macular degeneration and Stargardt disease. Lipofuscin bisretinoids (exemplified by N-retinylidene-N-retinylethanolamine) seem to mediate lipofuscin toxicity. Synthesis of lipofuscin bisretinoids depends on the influx of retinol from serum to the retina. Compounds antagonizing the retinol-dependent interaction of retinol-binding protein 4 (RBP4) with transthyretin in the serum would reduce serum RBP4 and retinol and inhibit bisretinoid formation. We recently showed that A1120 (3), a potent carboxylic acid based RBP4 antagonist, can significantly reduce lipofuscin bisretinoid formation in the retinas of Abca4(-/-). mice. As part of the NIH Blueprint Neurotherapeutics Network project we undertook the in vitro exploration to identify novel conformationally flexible and constrained RBP4 antagonists with improved potency and metabolic stability. We also demonstrate that upon acute and chronic dosing in rats, 43, a potent cyclopentyl fused pyrrolidine antagonist, reduced circulating plasma RBP4 protein levels by approximately 60%.

  DOI：

  10.1021/jm5010013

文献信息

• Hydrogel Prodrugs
  申请人：ASCENDIS PHARMA A/S

  公开号：US20150258205A1

  公开（公告）日：2015-09-17

  The present invention relates to a process for the preparation of a hydrogel and to a hydrogel obtainable by said process. The present invention further relates to a process for the preparation of a hydrogel-spacer conjugate, to a hydrogel-spacer conjugate obtainable by said process, to a process for the preparation of a carrier-linked prodrug and to carrier-linked prodrugs obtainable by said process, in particular to carrier-linked prodrugs that provide for a controlled or sustained release of a drug from a carrier. In addition, the invention relates to the use of the hydrogel for the preparation of a carrier-linked prodrug.

  本发明涉及一种制备水凝胶的方法，以及通过该方法可获得的水凝胶。本发明还涉及一种制备水凝胶-间隔物共轭物的方法，以及通过该方法可获得的水凝胶-间隔物共轭物，还涉及一种制备载体连结的前药的方法，以及通过该方法可获得的载体连结的前药，特别是提供了能够从载体中控制或持续释放药物的载体连结的前药。此外，本发明涉及使用水凝胶制备载体连结的前药。
• [EN] PROTECTING GROUP COMPRISING A PURIFICATION TAG<br/>[FR] GROUPE PROTECTEUR COMPRENANT UNE ÉTIQUETTE DE PURIFICATION
  申请人：ASCENDIS PHARMA AS

  公开号：WO2015052155A1

  公开（公告）日：2015-04-16

  The present invention relates to compounds comprising a protecting group moiety-tag moiety conjugate, a method of purification and monoconjugates obtained from such method of purification.

  本发明涉及包含保护基团-标记基团共轭物的化合物，以及一种纯化方法和从该纯化方法获得的单共轭物。
• [EN] RBP4 ANTAGONISTS FOR THE TREATMENT OF AGE-RELATED MACULAR DEGENERATION AND STARGARDT DISEASE<br/>[FR] ANTAGONISTES DE RBP4 POUR LE TRAITEMENT DE LA DÉGÉNÉRESCENCE MACULAIRE LIÉE À L'ÂGE ET DE LA MALADIE DE STARGARDT
  申请人：UNIV COLUMBIA

  公开号：WO2014160409A1

  公开（公告）日：2014-10-02

  A method for treating a disease characterized by excessive lipofuscin accumulation in the retina in a mammal afflicted therewith, comprising administering to the mammal an effective amount of a compound having the structure of any one of Formulas I- IV described herein, or a pharmaceutically acceptable salt thereof.

  本发明涉及一种治疗哺乳动物视网膜中过量脂褐质积累所致疾病的方法，包括向哺乳动物施用具有任一公式I-IV所述结构的化合物或其药学上可接受的盐的有效量。
• Biodegradable Polyethylene Glycol Based Water-Insoluble Hydrogels
  申请人：Rau Harald

  公开号：US20120156259A1

  公开（公告）日：2012-06-21

  The present invention relates to biodegradable polyethylene glycol based water-insoluble hydrogels comprising backbone moieties which are interconnected by hydrolytically degradable bonds, the backbone moieties further comprising reactive functional groups, wherein the water-insoluble hydrogel is further characterized in that the ratio between the time period for the complete degradation of the hydrogel by hydrolysis of the degradable bonds into water-soluble degradation products comprising one or more backbone moieties and the time period for the release of the first 10 mol-% of water-soluble degradation products comprising one or more backbone moieties based on the total amount of backbone moieties in the hydrogel is greater than 1 and equal to or less than 2. The invention further relates to conjugates of such hydrogels with ligands or ligating groups, prodrugs and pharmaceutical compositions as well as their use in a medicament.

  本发明涉及可生物降解的聚乙二醇基水不溶性水凝胶，其包含通过水解降解键相互连接的骨架基团，骨架基团进一步包括反应性功能团，其中水不溶性水凝胶的特征在于，通过水解降解可将可降解键分解为可溶于水的降解产物，包括一个或多个骨架基团，完全降解水凝胶所需的时间与基于水凝胶中所有骨架基团数量的第一个10摩尔％可溶性降解产物的释放时间之比大于1且小于等于2。本发明还涉及这种水凝胶与配体或配位基团的共轭物、前药和制药组合物以及它们在药物中的使用。
• Non-retinoid RBP4 antagonist for treatment of age-related macular degeneration and stargardt disease
  申请人：Petrukhin Konstantin

  公开号：US08980924B2

  公开（公告）日：2015-03-17

  A method for treating bisretinoid-mediated macular degeneration in a mammal afflicted therewith comprising administering to the mammal an effective amount of a compound having the structure: or an ester or a pharmaceutically acceptable salt thereof.

  一种治疗哺乳动物因双视黄醛介导的黄斑退化的方法，包括给予哺乳动物一种有效量的具有以下结构的化合物，或其酯或药学上可接受的盐。