(S)-诺氟西汀 | 878663-13-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 中文名称: (S)-诺氟西汀
• 英文名称: (S)-1-phthalimido-3-(4-trifluormethyl-phenoxy)-3-phenyl-propane
• 英文别名: 2-{(3S)-3-Phenyl-3-[4-(trifluoromethyl)phenoxy]propyl}-1H-isoindole-1,3(2H)-dione；2-[(3S)-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propyl]isoindole-1,3-dione
• CAS: 878663-13-9
• 化学式: C₂₄H₁₈F₃NO₃
• 分子量: 425.407
• InChiKey: HBVJWKXCFVAHNT-NRFANRHFSA-N

物化性质

• 熔点：
  115-117°C
• 沸点：
  545.9±50.0 °C(Predicted)
• 密度：
  1.329±0.06 g/cm3(Predicted)
• 溶解度：
  可溶于氯仿、可溶于二氯甲烷、乙酸乙酯

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  31
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  46.6
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (S)-诺氟西汀 在 肼 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 生成 (3S)-3-苯基-3-[4-(三氟甲基)苯氧基]-1-丙胺
  参考文献：
  名称：

  The Acid Ceramidase Is a SARS-CoV-2 Host Factor

  摘要：

  SARS-CoV-2的变异体，例如Delta或Omicron变异体，具有更高的传播率，加速了全球COVID-19大流行。因此，需要部署新的治疗策略。报道了通过氟西汀干扰病毒进入来抑制酸性鞘磷酸酶（ASM）的方法。在这里，我们描述了酸性酯酶作为氟西汀的另一个靶点。为了发现这些效果，我们合成了一种独立于ASM的氟西汀衍生物AKS466。高分辨率的SARS-CoV-2-RNA FISH和RTqPCR分析表明，AKS466降低了病毒基因表达。研究表明，SARS-CoV-2使用ORF3蛋白使溶酶体pH去酸化。然而，AKS488或氟西汀的处理降低了溶酶体pH。我们的生化结果表明，AKS466定位于感染细胞的内部溶酶体复制区域，并证明那里富集了病毒基因组、负链RNA和mRNA。氟西汀和AKS466均抑制酸性酯酶活性，导致内部溶酶体酰胺升高，并干扰病毒复制。此外，一种特异性酸性酯酶抑制剂Ceranib-2可以减少SARS-CoV-2的复制，最重要的是，外源性C6-酰胺的补充干扰了病毒的复制。这些结果支持酸性酯酶是SARS-CoV-2宿主因子的假设。

  DOI：

  10.3390/cells11162532
• 作为产物：
  描述：

  对三氟甲基苯酚 在 偶氮二甲酸二异丙酯 、 三苯基膦 、 sodium iodide 作用下， 以 四氢呋喃 、 二甲基亚砜 为溶剂， 反应 17.0h， 生成 (S)-诺氟西汀
  参考文献：
  名称：

  Stereoselective inhibition of serotonin re-uptake and phosphodiesterase by dual inhibitors as potential agents for depression

  摘要：

  Multi-target compounds where more than one functional activity is incorporated into the same molecule may have advantages in treating disease states. Selective serotonin re-uptake inhibitors (SSRIs)(a) (i.e., (R)- and (S)-norfluoxetine) were chemically linked to a PDE4 inhibitor via a five carbon bridge. The new dual PDE4 inhibitor/SSRIs (i.e., (R)-8 and (S)-8) showed moderately potent but highly selective serotonin re-uptake inhibition (IC50 values of 173 and 42 nM, respectively) in vitro. The dual PDE4 inhibitor/SSRIs (R)-8 and (S)-8 also inhibited PDE4D2 (i.e., K-i values of 106 and 253 nM, respectively). Due to the synergistic functional activity, PDE4 inhibitor/SSRIs may be effective in treating diseases such as depression. Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmc.2008.10.065

文献信息

• Modulators of Central Nervous System Neurotransmitters
  申请人：Cashman John

  公开号：US20080261967A1

  公开（公告）日：2008-10-23

  Disclosed are agents having pharmacological activity against cellular receptors and intracellular signaling, particularly receptors and signaling pathways of central nervous system (CNS) neurotransmitters. Also disclosed are related methods and compositions for the treatment or prevention of diseases or disorders using the agents.

  本发明涉及具有药理活性的药物，特别是针对细胞受体和细胞内信号传导的药物，尤其是中枢神经系统（CNS）神经递质的受体和信号通路。本发明还涉及使用这些药物的相关方法和组合物，用于治疗或预防疾病或障碍。
• MODULATORS OF CENTRAL NERVOUS SYSTEM NEUROTRANSMITTERS
  申请人：CASHMAN John

  公开号：US20130123253A1

  公开（公告）日：2013-05-16

  Disclosed are agents having pharmacological activity against cellular receptors and intracellular signaling, particularly receptors and signaling pathways of central nervous system (CNS) neurotransmitters. Also disclosed are related methods and compositions for the treatment or prevention of diseases or disorders using the agents.

  本发明涉及一种对细胞受体和细胞内信号传导具有药理活性的药剂，特别是针对中枢神经系统（CNS）神经递质的受体和信号通路。本发明还涉及使用这些药剂的相关方法和组合物，用于治疗或预防疾病或障碍。
• US8168635B2
  申请人：——

  公开号：US8168635B2

  公开（公告）日：2012-05-01
• Stereoselective inhibition of serotonin re-uptake and phosphodiesterase by dual inhibitors as potential agents for depression
  作者：John R. Cashman、Troy Voelker、Robert Johnson、Aaron Janowsky

  DOI：10.1016/j.bmc.2008.10.065

  日期：2009.1

  Multi-target compounds where more than one functional activity is incorporated into the same molecule may have advantages in treating disease states. Selective serotonin re-uptake inhibitors (SSRIs)(a) (i.e., (R)- and (S)-norfluoxetine) were chemically linked to a PDE4 inhibitor via a five carbon bridge. The new dual PDE4 inhibitor/SSRIs (i.e., (R)-8 and (S)-8) showed moderately potent but highly selective serotonin re-uptake inhibition (IC50 values of 173 and 42 nM, respectively) in vitro. The dual PDE4 inhibitor/SSRIs (R)-8 and (S)-8 also inhibited PDE4D2 (i.e., K-i values of 106 and 253 nM, respectively). Due to the synergistic functional activity, PDE4 inhibitor/SSRIs may be effective in treating diseases such as depression. Published by Elsevier Ltd.
• The Acid Ceramidase Is a SARS-CoV-2 Host Factor
  作者：Nina Geiger、Louise Kersting、Jan Schlegel、Linda Stelz、Sofie Fähr、Viktoria Diesendorf、Valeria Roll、Marie Sostmann、Eva-Maria König、Sebastian Reinhard、Daniela Brenner、Sibylle Schneider-Schaulies、Markus Sauer、Jürgen Seibel、Jochen Bodem

  DOI：10.3390/cells11162532

  日期：——

  SARS-CoV-2 variants such as the delta or omicron variants, with higher transmission rates, accelerated the global COVID-19 pandemic. Thus, novel therapeutic strategies need to be deployed. The inhibition of acid sphingomyelinase (ASM), interfering with viral entry by fluoxetine was reported. Here, we described the acid ceramidase as an additional target of fluoxetine. To discover these effects, we synthesized an ASM-independent fluoxetine derivative, AKS466. High-resolution SARS-CoV-2–RNA FISH and RTqPCR analyses demonstrate that AKS466 down-regulates viral gene expression. It is shown that SARS-CoV-2 deacidifies the lysosomal pH using the ORF3 protein. However, treatment with AKS488 or fluoxetine lowers the lysosomal pH. Our biochemical results show that AKS466 localizes to the endo-lysosomal replication compartments of infected cells, and demonstrate the enrichment of the viral genomic, minus-stranded RNA and mRNAs there. Both fluoxetine and AKS466 inhibit the acid ceramidase activity, cause endo-lysosomal ceramide elevation, and interfere with viral replication. Furthermore, Ceranib-2, a specific acid ceramidase inhibitor, reduces SARS-CoV-2 replication and, most importantly, the exogenous supplementation of C6-ceramide interferes with viral replication. These results support the hypotheses that the acid ceramidase is a SARS-CoV-2 host factor.

  SARS-CoV-2的变异体，例如Delta或Omicron变异体，具有更高的传播率，加速了全球COVID-19大流行。因此，需要部署新的治疗策略。报道了通过氟西汀干扰病毒进入来抑制酸性鞘磷酸酶（ASM）的方法。在这里，我们描述了酸性酯酶作为氟西汀的另一个靶点。为了发现这些效果，我们合成了一种独立于ASM的氟西汀衍生物AKS466。高分辨率的SARS-CoV-2-RNA FISH和RTqPCR分析表明，AKS466降低了病毒基因表达。研究表明，SARS-CoV-2使用ORF3蛋白使溶酶体pH去酸化。然而，AKS488或氟西汀的处理降低了溶酶体pH。我们的生化结果表明，AKS466定位于感染细胞的内部溶酶体复制区域，并证明那里富集了病毒基因组、负链RNA和mRNA。氟西汀和AKS466均抑制酸性酯酶活性，导致内部溶酶体酰胺升高，并干扰病毒复制。此外，一种特异性酸性酯酶抑制剂Ceranib-2可以减少SARS-CoV-2的复制，最重要的是，外源性C6-酰胺的补充干扰了病毒的复制。这些结果支持酸性酯酶是SARS-CoV-2宿主因子的假设。