ethyl 5-phenyl-1-(4-sulfamoylphenyl)-1H-pyrazole-3-carboxylate | 781663-70-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: ethyl 5-phenyl-1-(4-sulfamoylphenyl)-1H-pyrazole-3-carboxylate
• 英文别名: 1-(4-aminosulfonylphenyl)-3-ethoxycarbonyl-5-phenyl-1H-pyrazole；5-phenyl-1-(4-sulfamoylphenyl)-1H-pyrazole-3-carboxylic acid ethyl ester；ethyl 5-phenyl-1-(4-sulfamoylphenyl)pyrazole-3-carboxylate
• CAS: 781663-70-5
• 化学式: C₁₈H₁₇N₃O₄S
• 分子量: 371.417
• InChiKey: ALXQQOQOXOQEDX-UHFFFAOYSA-N

物化性质

• 沸点：
  593.8±60.0 °C(Predicted)
• 密度：
  1.36±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  26
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  113
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  ethyl 5-phenyl-1-(4-sulfamoylphenyl)-1H-pyrazole-3-carboxylate 在 锂硼氢 、 三苯基膦 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 87.5h， 生成 1-(4-aminosulfonylphenyl)-3-bromomethyl-5-phenyl-1H-pyrazole
  参考文献：
  名称：

  New COX-2/5-LOX Inhibitors:  Apoptosis-Inducing Agents Potentially Useful in Prostate Cancer Chemotherapy

  摘要：

  The arachidonic acid metabolizing enzymes cyclooxygenase-2 (COX-2) and lipoxygenases (LOXs) have been found to be implicated in a variety of cancers, including prostate cancer. To develop new therapeutic treatments, it therefore seemed interesting to design dual COX-2/5-LOX inhibitors. We report here the synthesis and in vitro pharmacological properties of diarylpyrazole derivatives that have in their structure key pharmacophoric elements to obtain optimal interaction with subsites of active pockets in both enzyme systems. Using a molecular modeling approach, a set of SAR data is proposed, highlighting the importance of the sulfonyl group of one of the aryl moieties in terms of proliferation inhibition and/or apoptosis induction.

  DOI：

  10.1021/jm0407761
• 作为产物：
  描述：

  磺胺 在 盐酸 、 sodium acetate 、 sodium nitrite 作用下， 以 乙醇 、 水 为溶剂， 反应 5.25h， 生成 ethyl 5-phenyl-1-(4-sulfamoylphenyl)-1H-pyrazole-3-carboxylate
  参考文献：
  名称：

  Development and Assessment of 1,5–Diarylpyrazole/Oxime Hybrids Targeting EGFR and JNK–2 as Antiproliferative Agents: A Comprehensive Study through Synthesis, Molecular Docking, and Evaluation

  摘要：

  我们设计、合成了新的 1,5 二甲基吡唑肟杂化衍生物（支架 A 和 B），并使用多种光谱方法验证了它们的纯度。利用已知表达表皮生长因子受体和 JNK-2 的五种癌细胞系，包括人结直肠腺癌细胞系 DLD-1、人宫颈癌细胞系 Hela、人白血病细胞系 K562、人胰腺细胞系 SUIT-2 和人肝癌细胞系 HepG2，对所有合成的化合物 7a-j、8a-j、9a-c 和 10a-c 的体外细胞毒性进行了生物学评估。与非肟同系物 7a-j 和 9a-c 相比，含肟化合物 8a-j 和 10a-c 的抗增殖活性更高。与索拉非尼相比，化合物 8d、8g、8i 和 10c 可抑制表皮生长因子受体，其 IC50 值在 8 到 21 µM 之间。化合物 8i 对 JNK-2 的抑制作用与索拉非尼一样有效，IC50 值为 1.0 µM。此外，在 Hela 细胞系的细胞周期分析中，化合物 8g 显示细胞周期停滞在 G2/M 期，而化合物 8i 则显示 S 期和 G2 期联合停滞。根据对接研究，肟杂化合物 8d、8g、8i 和 10c 在表皮生长因子受体结合位点的结合自由能为 -12.98 至 32.30 kcal/mol，而化合物 8d 和 8i 在 JNK-2 结合位点的结合自由能为 -9.16 至 -12.00 kcal/mol。

  DOI：

  10.3390/molecules28186521

文献信息

• New selective carbonic anhydrase IX inhibitors: Synthesis and pharmacological evaluation of diarylpyrazole-benzenesulfonamides
  作者：Tiphaine Rogez-Florent、Samuel Meignan、Catherine Foulon、Perrine Six、Abigaëlle Gros、Christine Bal-Mahieu、Claudiu T. Supuran、Andrea Scozzafava、Raphaël Frédérick、Bernard Masereel、Patrick Depreux、Amélie Lansiaux、Jean-François Goossens、Sébastien Gluszok、Laurence Goossens

  DOI：10.1016/j.bmc.2012.10.029

  日期：2013.3

  Carbonic anhydrase (CA) IX expression is increased upon hypoxia and has been proposed as a therapeutic target since it has been associated with poor prognosis, tumor progression and pH regulation. We report the synthesis and the pharmacological evaluation of a new class of human carbonic anhydrase (hCA) inhibitors, 4-(5-aryl-2-hydroxymethyl-pyrazol-1-yl)-benzenesulfonamides. A molecular modeling study

  碳酸酐酶（CA）IX的表达在缺氧时增加，并且由于与不良预后，肿瘤进展和pH调节相关，因此被提议作为治疗靶标。我们报告了新型的人类碳酸酐酶（hCA）抑制剂4-（5-芳基-2-羟甲基-吡唑-1-基）-苯磺酰胺类的合成和药理学评估。为了模拟这种新的酶抑制剂家族在hCA IX活性位点内的结合模式，进行了分子建模研究。药理研究表明，在参数纳摩尔范围内，hCA IX的抑制力很高。这项研究表明磺酰胺基在间位上的位置1-苯基吡唑的相对于我们的化合物的hCA II的选择性增加了hCA IX。使用阿霉素作为细胞毒剂并在选定的CA IX抑制剂存在下，对乳腺癌MDA-MB-231细胞进行了体外抗增殖筛选。结果表明，用1μMCA IX抑制剂将阿霉素在低氧环境中的细胞毒性效率（以IC 50值表示）恢复到20％的水平。
• PYRAZOLE INHIBITORS OF COX-2 AND SEH
  申请人：Hammock Bruce D.

  公开号：US20140038923A1

  公开（公告）日：2014-02-06

  The present invention provides compounds and compositions, e.g., a series of compounds wherein a 1,5-biarylpyrazole group is conjugated to a urea group by a non-cleavable covalent chain, that are useful as dual COX-2/sEH inhibitors. The compounds disclosed herein have activity associated with the arachidonate cascade. The activity of these compounds was demonstrated using a lipopolysaccharide (LPS) induced model of pain in the rat. The compounds of the present invention demonstrated superior anti-allodynic activity as compared to the same dose of celecoxib, i.e., a COX-2 inhibitor, also as compared to the same dose of t-AUCB, i.e., a sEH inhibitor, and also as compared to the co-administered same dose of both celecoxib and t-AUCB. The dual inhibitors of the present invention demonstrate enhanced in vivo anti-allodynic activity in a nociceptive behavioral assay. In addition, the compounds of the present invention also demonstrated to have potent anti-angiogenic effects toward endothelial cells (HUVEC) and inhibit angiogenesis in vitro, ex vivo and in vivo. The dual inhibitors of the present invention also demonstrate anti-angiogenic effect to slow breast tumor growth in vivo.

  本发明提供了化合物和组合物，例如一系列化合物，其中1,5-联苯吡唑基通过不可断裂的共价链与尿素基结合，这些化合物可用作双COX-2/sEH抑制剂。本文披露的化合物具有与花生四烯酸级联相关的活性。这些化合物的活性是使用大鼠脂多糖（LPS）诱导的疼痛模型进行证明的。与同等剂量的Celecoxib（即COX-2抑制剂）以及同等剂量的t-AUCB（即sEH抑制剂）相比，本发明的化合物表现出优越的抗痛觉过敏活性，也与同时给予的Celecoxib和t-AUCB的同等剂量相比。本发明的双重抑制剂在伤害性行为测定中显示出增强的体内抗痛觉过敏活性。此外，本发明的化合物还表现出对内皮细胞（HUVEC）具有强效的抗血管生成作用，并且在体外、体内和体内抑制血管生成。本发明的双重抑制剂还表现出抗血管生成效应，可以减缓体内乳腺肿瘤生长。
• [EN] LOCALLY BIOAVAILABLE DRUGS<br/>[FR] MÉDICAMENTS BIODISPONIBLES LOCALEMENT
  申请人：HU MING

  公开号：WO2016172159A1

  公开（公告）日：2016-10-27

  Drugs have been designed and developed with a structural motif allowing local bioavailability in the target organ but that are not broadly distributed at a concentration sufficient to illicit toxic side effects in non-targeted organs. The structural motif subjects the compound to be rapidly metabolized by metabolic enzymes before reaching the non-targeted organs.

  药物已经设计和开发出具有结构基元的特征，使其在目标器官中具有局部生物利用度，但在非目标器官中的浓度不足以引发毒性副作用。这种结构基元使化合物在到达非目标器官之前迅速被代谢酶代谢。
• Anti-inflammatory Exploration of Sulfonamide Containing Diaryl Pyrazoles with Promising COX-2 Selectivity and Enhanced Gastric Safety Profile
  作者：Laxmikant S. Pavase、Dhananjay V. Mane、Kamalkishor G. Baheti

  DOI：10.1002/jhet.3118

  日期：2018.4

  Novel sulfonamide containing diaryl pyrazoles were synthesized and were subsequently tested for their in vitro cyclooxygenase inhibitory assay. Compounds that showed promising in vitro COX‐2 IC50 values and selectivity indices were then evaluated for their in vivo anti‐inflammatory inhibition assay using standard carrageenan‐induced rat paw edema method. Two promising inhibitors were evaluated for

  合成了新型的含磺酰胺的二芳基吡唑，随后对其体外环氧合酶抑制试验进行了测试。然后，使用标准角叉菜胶诱导的大鼠爪水肿方法，对显示出令人满意的体外COX-2 IC 50值和选择性指数的化合物进行体内抗炎抑制分析。评价了两种有前途的抑制剂的致溃疡作用。COX-2的X射线晶体结构取自PDB条目COX-2（3LN1），分辨率为2.80Å（埃）。对接研究的结构准备工作是使用Maestro 9.0中的蛋白质准备向导完成的。化合物10b表现出合理的COX-2抑制作用（COX-2 IC50  = 0.52μM）和COX-2选择性指数（SI = 10.73）与塞来昔布（COX-2 IC 50  = 0.78μM）和（SI = 9.51）进行比较。体内抗炎研究显示10b的抑制率为64.28％，而塞来昔布本身的抑制率为57.14％。还发现致溃疡作用的结果与标准塞来昔布相当。分子对接研究表明，所有设计的分子均表现出与
• Pyrazole inhibitors of COX-2 and sEH
  申请人：Hammock Bruce D.

  公开号：US09096532B2

  公开（公告）日：2015-08-04

  The present invention provides compounds and compositions, e.g., a series of compounds wherein a 1,5-biarylpyrazole group is conjugated to a urea group by a non-cleavable covalent chain, that are useful as dual COX-2/sEH inhibitors. The compounds disclosed herein have activity associated with the arachidonate cascade. The activity of these compounds was demonstrated using a lipopolysaccharide (LPS) induced model of pain in the rat. The compounds of the present invention demonstrated superior anti-allodynic activity as compared to the same dose of celecoxib, i.e., a COX-2 inhibitor, also as compared to the same dose of t-AUCB, i.e., a sEH inhibitor, and also as compared to the co-administered same dose of both celecoxib and t-AUCB. The dual inhibitors of the present invention demonstrate enhanced in vivo anti-allodynic activity in a nociceptive behavioral assay. In addition, the compounds of the present invention also demonstrated to have potent anti-angiogenic effects toward endothelial cells (HUVEC) and inhibit angiogenesis in vitro, ex vivo and in vivo. The dual inhibitors of the present invention also demonstrate anti-angiogenic effect to slow breast tumor growth in vivo.

  本发明提供了一系列化合物和组合物，例如一系列化合物，其中1,5-双芳基吡唑基团通过不可切断的共价链与尿素基团共轭，这些化合物对于作为双重COX-2 / sEH抑制剂是有用的。本文所述化合物具有与花生四烯酸级联相关的活性。这些化合物的活性是使用大鼠脂多糖（LPS）诱导的疼痛模型进行证明的。与同剂量的COX-2抑制剂Celecoxib，即与同剂量的sEH抑制剂t-AUCB以及同时共同给予的Celecoxib和t-AUCB相比，本发明的化合物表现出优越的抗痛觉过敏活性。本发明的双重抑制剂在伤害感知行为测定中表现出增强的体内抗痛觉过敏活性。此外，本发明的化合物还展示了对内皮细胞（HUVEC）具有强效的抗血管生成作用，并在体外、体内和体外抑制血管生成。本发明的双重抑制剂还表现出抗血管生成作用，以减缓体内乳腺肿瘤生长。