Methyl 2-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carboxamido)benzoate | 1482429-12-8

• 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: Methyl 2-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carboxamido)benzoate
• 英文别名: methyl 2-[[4-[2-(trifluoromethyl)phenyl]piperidine-1-carbonyl]amino]benzoate
• CAS: 1482429-12-8
• 化学式: C₂₁H₂₁F₃N₂O₃
• 分子量: 406.405
• InChiKey: KQGWZWJXRAHHCY-UHFFFAOYSA-N

物化性质

• 沸点：
  549.1±50.0 °C(Predicted)
• 密度：
  1.303±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  58.6
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  Methyl 2-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carboxamido)benzoate 在 sodium hydroxide 、 盐酸 作用下， 以 四氢呋喃 、 甲醇 、 氘代甲醇 、 水 为溶剂， 反应 2.0h， 以95%的产率得到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
• 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 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 为溶剂， 反应 9.08h， 生成 Methyl 2-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carboxamido)benzoate
  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

• NON-RETINOID ANTAGONISTS FOR TREATMENT OF AGE-RELATED MACULAR DEGENERATION AND STARGARDT DISEASE
  申请人：Petrukhin Konstantin

  公开号：US20150126494A1

  公开（公告）日：2015-05-07

  A method for treating a disease characterized by excessive lipofuscin accumulation in the retina in mammals afflicted therewith, comprising administering to the mammal an effective amount of a non-retinoid antagonist compound or a pharmaceutically acceptable salt thereof.
• US9333202B2
  申请人：——

  公开号：US9333202B2

  公开（公告）日：2016-05-10
• Design, Synthesis, and Evaluation of Nonretinoid Retinol Binding Protein 4 Antagonists for the Potential Treatment of Atrophic Age-Related Macular Degeneration and Stargardt Disease
  作者：Christopher L. Cioffi、Nicoleta Dobri、Emily E. Freeman、Michael P. Conlon、Ping Chen、Douglas G. Stafford、Daniel M. C. Schwarz、Kathy C. Golden、Lei Zhu、Douglas B. Kitchen、Keith D. Barnes、Boglarka Racz、Qiong Qin、Enrique Michelotti、Charles L. Cywin、William H. Martin、Paul G. Pearson、Graham Johnson、Konstantin Petrukhin

  DOI：10.1021/jm5010013

  日期：2014.9.25

  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%.