4'-羟基氟比洛芬 | 52807-12-2

• 物质功能分类: 分析化学 - 标准品 - 药典标准品和杂质标准品
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 4'-羟基氟比洛芬
• 中文别名: 4-羟基氟吡洛芬
• 英文名称: 2-(2-fluoro-4'-hydroxy-biphenyl-4-yl)-propionic acid
• 英文别名: 4'-Hydroxyflurbiprofen；2-(2-fluoro-4′-hydroxy-[1,1′-biphenyl]-4-yl)propanoic acid；2-(2-fluoro-4'-hydroxybiphenyl-4-yl)propanoic acid；4’-hydroxyflurbiprofen；4'-hydroxy-flurbiprofen；2-[3-fluoro-4-(4-hydroxyphenyl)phenyl]propanoic acid
• CAS: 52807-12-2
• 化学式: C₁₅H₁₃FO₃
• 分子量: 260.265
• InChiKey: GTSMMBJBNJDFRA-UHFFFAOYSA-N

物化性质

• 熔点：
  177-178°C
• 沸点：
  417.6±40.0 °C(Predicted)
• 密度：
  1.288±0.06 g/cm3(Predicted)
• 溶解度：
  DMF：25mg/mL； DMSO：10mg/mL；乙醇：25mg/mL； PBS（pH 7.2）：0.5 mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  19
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  57.5
• 氢给体数：
  2
• 氢受体数：
  4

安全信息

• 海关编码：
  2922299090
• 储存条件：
  -20°C，密闭保存，并保持干燥。

制备方法与用途

4′-羟基氟比洛芬是cox抑制剂氟比洛芬及其对映体(R)-氟比洛芬和(S)-氟比洛芬的主要活性代谢物。

反应信息

• 作为反应物：
  描述：

  4'-羟基氟比洛芬 在 lithium hydroxide monohydrate 、 硫酸 、 水 、 potassium carbonate 、 silver nitrate 、 N,N'-二环己基碳二亚胺 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 57.5h， 生成 6-{2'-fluoro-4'-[1-oxo-1-(4-(1,2,3,4-tetrahydroacridin-9-ylamino)butylamino)propan-2-yl]biphenyl-4-yloxy}hexyl nitrate
  参考文献：
  名称：

  NO-donating tacrine derivatives as potential butyrylcholinesterase inhibitors with vasorelaxation activity

  摘要：

  To search for potent anti-Alzheimer's disease (AD) agents with multifunctional effects, 12 NO-donating tacrine-flurbiprofen hybrid compounds (2a-l) were synthesized and biologically evaluated. It was found that all the new target compounds showed selective butyrylcholinesterase (BuChE) inhibitory activity in vitro comparable or higher than tacrine and the tacrine-flurbiprofen hybrid compounds 1a-c, and released moderate amount of NO in vitro. The kinetic study suggests that one of the most active and highest BuChE selective compounds 2d may not only compete with the substrate for the same catalytic active site (CAS) but also interact with a second binding site. Furthermore, 2d and 2l exhibited significant vascular relaxation effect, which is beneficial for the treatment of AD. All the results suggest that 2d and 2l might be promising lead compounds for further research. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.04.008
• 作为产物：
  描述：

  氟比洛芬 在 aluminum (III) chloride 、 硫酸 、 间氯过氧苯甲酸 、 potassium hydroxide 作用下， 以 甲醇 、 二氯甲烷 、 水 为溶剂， 反应 34.0h， 生成 4'-羟基氟比洛芬
  参考文献：
  名称：

  发现4'-OH-氟比洛芬曼尼希碱衍生物是具有多种抑制活性的潜在阿尔茨海默氏病治疗药物。

  摘要：

  设计，合成和评估了一系列4'-OH氟比洛芬曼尼希碱衍生物，作为治疗阿尔茨海默氏病的潜在多功能剂。生物学筛选结果表明，这些衍生物大多数表现出良好的多功能活性。其中，化合物8n对自诱导的Aβ1-42聚集表现出最佳的抑制作用（在25.0μM时为65.03％）。此外，该代表性化合物在体外还表现出良好的抗氧化活性，生物金属螯合能力和抗神经炎活性。此外，化合物8n显示出适当的血脑屏障渗透性。这些多功能特性突出了化合物8n作为抗AD多功能药物进一步开发的有希望的候选物。

  DOI：

  10.1016/j.bmc.2019.01.040

文献信息

• Isoxazole derivatives
  申请人：Sumitomo Pharmaceutical Company, Limited

  公开号：US06100260A1

  公开（公告）日：2000-08-08

  An isoxazole derivative represented by the formula: ##STR1## or a pharmaceutically acceptable salt thereof useful as a therapeutic drug for auto-immune diseases and inflammatory diseases.

  一种由以下结构表示的异噁唑衍生物：##STR1##或其药用可接受的盐，用作治疗自身免疫疾病和炎症性疾病的药物。
• CYP2C9 Genotype-Dependent Effects on in Vitro Drug-Drug Interactions: Switching of Benzbromarone Effect from Inhibition to Activation in the CYP2C9.3 Variant
  作者：Matthew A. Hummel、Charles W. Locuson、Peter M. Gannett、Dan A. Rock、Carrie M. Mosher、Allan E. Rettie、Timothy S. Tracy

  DOI：10.1124/mol.105.013763

  日期：2005.9

  The CYP2C9.3 variant exhibits marked decreases in substrate turnover compared with the wild-type enzyme, but little is known regarding the effect this variant form may have on the occurrence of drug-drug interactions. To examine this possibility, the effect of the potent CYP2C9 inhibitor, benzbromarone, was studied with regard to CYP2C9.1- and CYP2C9.3-mediated flurbiprofen metabolism to evaluate whether the variant enzyme exhibits differential inhibition kinetics. Although benzbromarone inhibited CYP2C9.1 activity as expected, CYP2C9.3-mediated flurbiprofen 4′-hydroxylation was activated in the presence of benzbromarone. T1 relaxation studies revealed little change in distances of flurbiprofen protons from the heme iron of either CYP2C9.1 or CYP2C9.3 in the presence of benzbromarone compared with flurbiprofen alone. Spectral binding studies were also performed to investigate whether benzbromarone affected substrate binding, with the addition of benzbromarone having little effect on flurbiprofen-binding affinity in both CYP2C9.1 and CYP2C9.3. Docking studies with the 2C9.1 structure crystallized with a closed active site identified multiple but overlapping subsites with sufficient space for benzbromarone binding in the enzyme when flurbiprofen was positioned closest to the heme. If the closed conformation of 2C9.3 is structurally similar to 2C9.1, as expected for the conservative I359L mutation, then the dynamics of benzbromarone binding may account for the switching of drug interaction effects. In conclusion, the I359L amino acid substitution found in CYP2C9.3 not only reduces metabolism compared with CYP2C9.1 but can also dramatically alter inhibitor effects, suggesting that differential degrees of drug inhibition interactions may occur in individuals with this variant form of CYP2C9.

  与野生型酶相比，CYP2C9.3变体的底物周转率明显下降，但人们对这种变体形式可能对发生药物间相互作用的影响知之甚少。为了研究这种可能性，我们研究了强效 CYP2C9 抑制剂苯溴马隆对 CYP2C9.1 和 CYP2C9.3 介导的氟比洛芬代谢的影响，以评估变异酶是否表现出不同的抑制动力学。尽管苯溴马隆抑制了 CYP2C9.1 的活性，但在苯溴马隆存在的情况下，CYP2C9.3 介导的氟比洛芬 4′-羟基化被激活。T1 驰豫研究显示，与单独使用氟比洛芬相比，在有苯溴马隆存在的情况下，氟比洛芬质子与 CYP2C9.1 或 CYP2C9.3 血红素铁的距离变化不大。此外，还进行了光谱结合研究，以调查苯溴马隆是否会影响底物的结合，在 CYP2C9.1 和 CYP2C9.3 中，添加苯溴马隆对氟比洛芬的结合亲和力几乎没有影响。利用封闭活性位点结晶的 2C9.1 结构进行的对接研究发现，当氟比洛芬最靠近血红素时，该酶中有多个但相互重叠的亚位点，有足够的空间与苯溴马隆结合。如果 2C9.3 的封闭构象在结构上类似于 2C9.1，正如保守的 I359L 突变所预期的那样，那么苯溴马隆结合的动力学可能是药物相互作用效应转换的原因。总之，与 CYP2C9.1 相比，在 CYP2C9.3 中发现的 I359L 氨基酸替代不仅会降低代谢，而且还会显著改变抑制剂的效果，这表明在具有这种变异形式 CYP2C9 的个体中可能会出现不同程度的药物抑制相互作用。
• Method and composition for treating neurodegenerative disorders
  申请人：Hobden Adrian

  公开号：US20050288375A1

  公开（公告）日：2005-12-29

  The invention provides compositions and methods for treating neurodegenerative disorders. A method of the invention involves administering to an individual in need of treatment a composition having an R-NSAID and an NMDA antagonist. Another method of the invention involves administering to an individual in need of treatment a composition having at least two compounds that are capable of interacting with CYP2C9, wherein at least one of said compounds is an Aβ 42 lowering agent. The methods and compositions of the invention are useful for treating and preventing neurodegenerative disorders like Alzheimer's disease, dementia, mild cognitive impairment.

  本发明提供了用于治疗神经退行性疾病的组合物和方法。该发明的一种方法涉及向需要治疗的个体施用具有R-NSAID和NMDA拮抗剂的组合物。该发明的另一种方法涉及向需要治疗的个体施用至少两种能够与CYP2C9相互作用的化合物的组合物，其中至少一种化合物是Aβ42降低剂。该发明的方法和组合物对于治疗和预防像阿尔茨海默病、痴呆症、轻度认知障碍等神经退行性疾病非常有用。
• Synthesis and Biological Activity of Flurbiprofen Analogues as Selective Inhibitors of β-Amyloid₁_-₄₂ Secretion
  作者：Ilaria Peretto、Stefano Radaelli、Carlo Parini、Michele Zandi、Luca F. Raveglia、Giulio Dondio、Laura Fontanella、Paola Misiano、Chiara Bigogno、Andrea Rizzi、Benedetta Riccardi、Marcello Biscaioli、Silvia Marchetti、Paola Puccini、Silvia Catinella、Ivano Rondelli、Valentina Cenacchi、Pier Tonino Bolzoni、Paola Caruso、Gino Villetti、Fabrizio Facchinetti、Elda Del Giudice、Nadia Moretto、Bruno P. Imbimbo

  DOI：10.1021/jm0502541

  日期：2005.9.1

  Flurbiprofen, a nonsteroidal antiinflammatory drug (NSAID), has been recently described to selectively inhibit beta-amyloid(1-42) (A beta 42) secretion, the most toxic component of the senile plaques present in the brain of Alzheimer patients. The use of this NSAID in Alzheimer's disease (AD) is hampered by a significant gastrointestinal toxicity associated with cyclooxygenase (COX) inhibition. New flurbiprofen analogues were synthesized, with the aim of increasing A beta 42 inhibitory potency while removing anti-COX activity. In vitro ADME developability parameters were taken into account in order to identify optimized compounds at an early stage of the project. Appropriate substitution patterns at the alpha position of flurbiprofen allowed for the complete removal of anti-COX activity, while modifications at the terminal phenyl ring resulted in increased inhibitory potency on A beta 42 secretion. In rats, some of the compounds appeared to be well absorbed after oral administration and to penetrate into the central nervous system. Studies in a transgenic mice model of AD showed that selected compounds significantly decreased plasma A beta 42 concentrations. These new flurbiprofen analogues represent potential drug candidates to be developed for the treatment of AD.
• DE2329125
  申请人：——

  公开号：——

  公开（公告）日：——