5-hydroxy-2-((4-(trifluoromethyl)benzyl)oxy)benzaldehyde | 1311393-11-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 5-hydroxy-2-((4-(trifluoromethyl)benzyl)oxy)benzaldehyde
• 英文别名: 5-Hydroxy-2-[[4-(trifluoromethyl)phenyl]methoxy]benzaldehyde
• CAS: 1311393-11-9
• 化学式: C₁₅H₁₁F₃O₃
• 分子量: 296.246
• InChiKey: RBDRLRDXAJDWNZ-UHFFFAOYSA-N

物化性质

• 沸点：
  419.4±40.0 °C(Predicted)
• 密度：
  1.360±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  21
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  46.5
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  5-hydroxy-2-((4-(trifluoromethyl)benzyl)oxy)benzaldehyde 在 sodium hydride 、 caesium carbonate 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.5h， 生成 ethyl (2E)-2-(5-{[4-chloro-2-(trifluoromethyl)quinolin-6-yl]methoxy}-2-{[4-(trifluoromethyl)benzyl]oxy}benzylidene)hexanoate
  参考文献：
  名称：

  SAR-studies of γ-secretase modulators with PPARγ-agonistic and 5-lipoxygenase-inhibitory activity for Alzheimer’s disease

  摘要：

  We present the design, synthesis and biological evaluation of compounds containing a 2-(benzylidene) hexanoic acid scaffold as multi-target directed gamma-secretase-modulators. Broad structural variations were undertaken to elucidate the structure-activity-relationships at the 5-position of the aromatic core. Compound 13 showed the most potent activity profile with IC50 values of 0.79 mu M (Ab42), 0.3 mu M (5-lipoxygenase) and an EC50 value of 4.64 mu M for PPAR gamma-activation. This derivative is the first compound exhibiting low micromolar to nanomolar activities for these three targets. Combining gamma-secretase-modulation, PPAR gamma-agonism and inhibition of 5-lipoxygenase in one compound could be a novel diseasemodifying multi-target-strategy for Alzheimer's disease to concurrently address the causative amyloid pathology and secondary pathologies like chronic brain inflammation. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.12.073
• 作为产物：
  描述：

  2,5-二羟基苯甲醛 、 1-溴-三氟对二甲苯 在 caesium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.25h， 以60%的产率得到5-hydroxy-2-((4-(trifluoromethyl)benzyl)oxy)benzaldehyde
  参考文献：
  名称：

  新型PPARγ拮抗剂的结构优化。

  摘要：

  过氧化物酶体增殖物激活受体γ（PPARγ）调节剂已发现广泛用于治疗癌症，代谢紊乱和炎症性疾病。与PPARγ激动剂相反，对PPARγ拮抗剂的研究较少，尽管它们显示出免疫调节作用，但市场上仍没有治疗上有用的PPARγ拮抗剂。相反引起的2-氯-5-硝基苯甲酰苯胺（GW9662）非竞争性的，不可逆抑制，则最近描述（Ë）-2-（5-（（4-甲氧基-2-（三氟甲基）喹啉-6-基）甲氧基）-2-（（4-（三氟甲基）苄基氧基）-亚苄基）己酸（MTTB，T -10017）是新型PPARγ拮抗剂的有希望的原型。在HEK293T细胞的反式激活测定中，它对罗格列酮介导的PPARγ配体结合域（PPARγLBD）的活化具有竞争性拮抗作用，对1 µM罗格列酮的IC 50为4.3 µM。这项研究的目的是研究MTTB支架的结构-活性关系（SAR），重点是改善其理化特性。通过这种优化，制备并表征了34种新的衍生物。鉴定了两种

  DOI：

  10.1016/j.bmc.2019.115082

文献信息

• Design, Synthesis, and Evaluation of Dihydropyranopyrazole Derivatives as Novel PDE2 Inhibitors for the Treatment of Alzheimer’s Disease
  作者：Yan Zhou、Jinjian Li、Han Yuan、Rui Su、Yue Huang、Yi-You Huang、Zhe Li、Yinuo Wu、Hai-Bin Luo、Chen Zhang、Ling Huang

  DOI：10.3390/molecules26103034

  日期：——

  2 (PDE2) has been regarded as a novel target for the treatment of Alzheimer’s disease (AD). In this study, we obtained (R)-LZ77 as a hit compound with moderate PDE2 inhibitory activity (IC50 = 261.3 nM) using a high-throughput virtual screening method based on molecular dynamics. Then, we designed and synthesized 28 dihydropyranopyrazole derivatives as PDE2 inhibitors. Among them, compound (+)-11h was

  磷酸二酯酶2（PDE2）已被视为治疗阿尔茨海默氏病（AD）的新型靶标。在这项研究中，我们获得了（- [R ）- LZ77作为中度PDE2抑制活性（IC命中化合物50使用基于分子动力学高通量虚拟筛选方法= 261.3纳米）。然后，我们设计并合成了28种二氢吡喃并吡唑衍生物作为PDE2抑制剂。其中，化合物（+）- 11h是最有效的PDE2抑制剂，IC 50值为41.5 nM。PDE2-（+）- 11h的分子对接揭示了该化合物的4-（三氟甲基）苄基）氧基侧链进入H型口袋并与L770 / L809 / F862形成强疏水相互作用，从而提高了抑制活性。以上结果可为进一步高效优化PDE2抑制剂的结构提供见识，并可为其在AD治疗中的应用奠定基础。
• Discovery and Biological Evaluation of a Novel Class of Dual Microsomal Prostaglandin E₂ Synthase-1/5-lipoxygenase Inhibitors Based on 2-[(4,6-Diphenethoxypyrimidin-2-yl)thio]hexanoic Acid
  作者：Martina Hieke、Christine Greiner、Michaela Dittrich、Felix Reisen、Gisbert Schneider、Manfred Schubert-Zsilavecz、Oliver Werz

  DOI：10.1021/jm200092b

  日期：2011.7.14

  Various inflammatory diseases are associated with the excessive formation of leukotrienes (LTs) and prostaglandins (PGs). Herein, we present a novel class of dual inhibitors of 5-lipoxygenase (5-LO) and microsomal prostaglandin E-2 synthase-1 (mPGES-1), key enzymes in the formation of LTs and PGE(2), respectively. On the basis of the structure of 2-[(4,6-diphenethoxypyrimidin-2-yl-)thio]hexanoic acid (1), we performed a detailed SAR analysis, and mechanistic studies were carried out to elucidate the mode of 5-LO inhibition. Interestingly, the pyrimidine ring including the thioether of 1 could be replaced by a simple benzyl or a benzylidene moiety yielding a novel series of bioactive 2-benzylidene- and 2-benzylhexanoic acids exemplified by 2-(2,3-diphenethoxybenzylidene)hexanoic acid, 29 (IC50 5-LO = 0.8 mu M; mPGES-1 = 1.1 mu M). Importantly, none of the novel bioactive derivatives strongly inhibited cyclooxygenase activities. Together, we provide novel promising lead compounds for the treatment of inflammatory diseases valuable for further investigations in vivo.
• Structure optimization of a new class of PPARγ antagonists
  作者：Victor Hernandez-Olmos、Tilo Knape、Jan Heering、Andreas von Knethen、Whitney Kilu、Astrid Kaiser、Mario Wurglics、Moritz Helmstädter、Daniel Merk、Manfred Schubert-Zsilavecz、Michael J. Parnham、Dieter Steinhilber、Ewgenij Proschak

  DOI：10.1016/j.bmc.2019.115082

  日期：2019.11

  the recently described (E)-2-(5-((4-methoxy-2-(trifluoromethyl)quinolin-6-yl)methoxy)-2-((4-(trifluoromethyl)benzyl)oxy)-benzylidene)-hexanoic acid (MTTB, T-10017) is a promising prototype for a new class of PPARγ antagonists. It exhibits competitive antagonism against rosiglitazone mediated activation of PPARγ ligand binding domain (PPARγLBD) in a transactivation assay in HEK293T cells with an IC50

  过氧化物酶体增殖物激活受体γ（PPARγ）调节剂已发现广泛用于治疗癌症，代谢紊乱和炎症性疾病。与PPARγ激动剂相反，对PPARγ拮抗剂的研究较少，尽管它们显示出免疫调节作用，但市场上仍没有治疗上有用的PPARγ拮抗剂。相反引起的2-氯-5-硝基苯甲酰苯胺（GW9662）非竞争性的，不可逆抑制，则最近描述（Ë）-2-（5-（（4-甲氧基-2-（三氟甲基）喹啉-6-基）甲氧基）-2-（（4-（三氟甲基）苄基氧基）-亚苄基）己酸（MTTB，T -10017）是新型PPARγ拮抗剂的有希望的原型。在HEK293T细胞的反式激活测定中，它对罗格列酮介导的PPARγ配体结合域（PPARγLBD）的活化具有竞争性拮抗作用，对1 µM罗格列酮的IC 50为4.3 µM。这项研究的目的是研究MTTB支架的结构-活性关系（SAR），重点是改善其理化特性。通过这种优化，制备并表征了34种新的衍生物。鉴定了两种
• SAR-studies of γ-secretase modulators with PPARγ-agonistic and 5-lipoxygenase-inhibitory activity for Alzheimer’s disease
  作者：Daniel Flesch、Julia Ness、Christina Lamers、Friederike Dehm、Sven Popella、Ramona Steri、Isabella Ogorek、Martina Hieke、Gerd Dannhardt、Oliver Werz、Sascha Weggen、Manfred Schubert-Zsilavecz

  DOI：10.1016/j.bmcl.2014.12.073

  日期：2015.2

  We present the design, synthesis and biological evaluation of compounds containing a 2-(benzylidene) hexanoic acid scaffold as multi-target directed gamma-secretase-modulators. Broad structural variations were undertaken to elucidate the structure-activity-relationships at the 5-position of the aromatic core. Compound 13 showed the most potent activity profile with IC50 values of 0.79 mu M (Ab42), 0.3 mu M (5-lipoxygenase) and an EC50 value of 4.64 mu M for PPAR gamma-activation. This derivative is the first compound exhibiting low micromolar to nanomolar activities for these three targets. Combining gamma-secretase-modulation, PPAR gamma-agonism and inhibition of 5-lipoxygenase in one compound could be a novel diseasemodifying multi-target-strategy for Alzheimer's disease to concurrently address the causative amyloid pathology and secondary pathologies like chronic brain inflammation. (C) 2014 Elsevier Ltd. All rights reserved.