2-methyl-5-[4-(methylsulfonyl)phenyl]-1-[3-(fluoro)phenyl]-1H-pyrrole

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: 2-methyl-5-[4-(methylsulfonyl)phenyl]-1-[3-(fluoro)phenyl]-1H-pyrrole
• 英文别名: 1-(3-fluorophenyl)-2-methyl-5-(4-(methylsulfonyl)phenyl)-1H-pyrrole；1-(3-Fluorophenyl)-2-methyl-5-(4-methylsulfonylphenyl)pyrrole
• 化学式: C₁₈H₁₆FNO₂S
• 分子量: 329.395
• InChiKey: ZSGARAVUFWYACK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  47.4
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-methyl-5-[4-(methylsulfonyl)phenyl]-1-[3-(fluoro)phenyl]-1H-pyrrole 在 三乙基硅烷 、 4-二甲氨基吡啶 、 水 、 四氯化钛 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三氟乙酸 、 sodium hydroxide 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 4.5h， 生成 3-(nitroxy)propyl-[1-(3-fluorophenyl)-2-methyl-5-(4-methylsulphonylphenyl)-1H-pyrrol-3-yl]-acetate
  参考文献：
  名称：

  Novel Analgesic/Anti-Inflammatory Agents: Diarylpyrrole Acetic Esters Endowed with Nitric Oxide Releasing Properties

  摘要：

  The design of compounds that are able to inhibit cyclooxygenase (COX) and to release nitric oxide (NO) should give rise to drugs endowed with an overall safer profile for the gastrointestinal and cardiovascular systems. Herein we report a new class of pyrrole-derived nitrooxy esters (11a-j), cyclooxygenase-2 (COX-2) selective inhibitors endowed with NO releasing properties, with the goal of generating new molecules able to both strongly inhibit this isoform and reduce the related adverse side effects. Taking into account the metabolic conversion of nitrooxy esters into corresponding alcohols, we also studied derivatives 12a-j. All compounds proved to be very potent and selective COX-2 inhibitors; nitrooxy derivatives displayed interesting ex vivo NO-dependent vasorelaxing properties. Compounds 11c, 11d, 12c, and 12d were selected for further in vivo studies that highlited good anti-inflammatory and antinociceptive activities. Finally, two selected compounds (11c and 12c) tested in human whole blood (HWB) assay proved to be preferential inhibitors of COX-2.

  DOI：

  10.1021/jm200715n
• 作为产物：
  描述：

  1-[4-(甲硫基)苯基]-1,4-戊烷二酮 在 potassium peroxymonosulfate 、 对甲苯磺酸 作用下， 以 甲醇 、 乙醇 、 水 为溶剂， 160.0 ℃ 、1.03 MPa 条件下， 反应 2.75h， 生成 2-methyl-5-[4-(methylsulfonyl)phenyl]-1-[3-(fluoro)phenyl]-1H-pyrrole
  参考文献：
  名称：

  Improving the solubility of a new class of antiinflammatory pharmacodynamic hybrids, that release nitric oxide and inhibit cycloxygenase-2 isoenzyme

  摘要：

  The development of a novel class of pharmacodynamic hybrids that inhibits COX-2 isoform is reported. These molecules display enhanced nitric oxide releasing properties due to the presence of an ionisable moiety. The in vivo analgesic/anti-inflammatory activity was maintained in relation to the parent compounds. (c) 2012 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2012.10.014

文献信息

• Novel Ester and Acid Derivatives of the 1,5-Diarylpyrrole Scaffold as Anti-Inflammatory and Analgesic Agents. Synthesis and in Vitro and in Vivo Biological Evaluation
  作者：Mariangela Biava、Giulio C. Porretta、Giovanna Poce、Claudio Battilocchio、Fabrizio Manetti、Maurizio Botta、Stefano Forli、Lidia Sautebin、Antonietta Rossi、Carlo Pergola、Carla Ghelardini、Nicoletta Galeotti、Francesco Makovec、Antonio Giordani、Paola Anzellotti、Paola Patrignani、Maurizio Anzini

  DOI：10.1021/jm901269y

  日期：2010.1.28

  (COX-2) inhibitors (coxibs) was developed to circumvent the major side effects of cyclooxygenase-1 (COX-1) and COX-2 inhibitors (stomach ulceration and nephrotoxicity). As a consequence, coxibs are extremely valuable in treating acute and chronic inflammatory conditions. However, the use of coxibs, such as rofecoxib (Vioxx), was discontinued because of the high risk of cardiovascular adverse events. More

  开发了新一代的选择性环氧合酶2（COX-2）抑制剂（coxibs），以规避环氧合酶1（COX-1）和COX-2抑制剂的主要副作用（胃溃疡和肾毒性）。结果，考昔布在治疗急性和慢性炎性疾病中非常有价值。但是，由于心血管不良事件的高风险，已停止使用罗非昔布（Vioxx）等考昔布。最近的临床发现强调了通过适当的COX-1与COX-2选择性可以如何缓解Coxib的心血管毒性。我们先前报道了一组对COX-2有选择性的取代的1,5-二芳基吡咯衍生物。在这里，我们描述了新的1,5-二芳基吡咯的合成及其在体外，离体的抑制作用，以及体内对COX同工酶及其止痛活性的研究。异丙基-2-甲基-5- [4-（甲基磺酰基）苯基] -1-苯基-1选择该系列的代表成员H-吡咯-3-乙酸酯（10a）进行药代动力学和代谢研究。
• Improving the solubility of a new class of antiinflammatory pharmacodynamic hybrids, that release nitric oxide and inhibit cycloxygenase-2 isoenzyme
  作者：Mariangela Biava、Claudio Battilocchio、Giovanna Poce、Salvatore Alfonso、Sara Consalvi、Giulio Cesare Porretta、Silvia Schenone、Vincenzo Calderone、Alma Martelli、Lara Testai、Carla Ghelardini、Lorenzo Di Cesare Mannelli、Lidia Sautebin、Antonietta Rossi、Antonio Giordani、Paola Patrignani、Maurizio Anzini

  DOI：10.1016/j.ejmech.2012.10.014

  日期：2012.12

  The development of a novel class of pharmacodynamic hybrids that inhibits COX-2 isoform is reported. These molecules display enhanced nitric oxide releasing properties due to the presence of an ionisable moiety. The in vivo analgesic/anti-inflammatory activity was maintained in relation to the parent compounds. (c) 2012 Elsevier Masson SAS. All rights reserved.
• Cyclooxygenase-2 Inhibitors. 1,5-Diarylpyrrol-3-acetic Esters with Enhanced Inhibitory Activity toward Cyclooxygenase-2 and Improved Cyclooxygenase-2/Cyclooxygenase-1 Selectivity
  作者：Mariangela Biava、Giulio Cesare Porretta、Giovanna Poce、Sibilla Supino、Stefano Forli、Michele Rovini、Andrea Cappelli、Fabrizio Manetti、Maurizio Botta、Lidia Sautebin、Antonietta Rossi、Carlo Pergola、Carla Ghelardini、Elisa Vivoli、Francesco Makovec、Paola Anzellotti、Paola Patrignani、Maurizio Anzini

  DOI：10.1021/jm0707525

  日期：2007.11.1

  The important role of cyclooxygenase-2 (COX-2) in the pathogenesis of inflammation and side effect limitations of current COX-2 inhibitor drugs illustrates a need for the design of new con pounds based on alternative structural templates. We previously reported a set of substituted 1,5-diarylpyrrole derivatives, along with their inhibitory activity toward COX enzymes. Several compounds proved to be highly selective COX-2 inhibitors and their affinity data were rationalized through docking simulations. In this paper, we describe the synthesis of new 1,5-diary lpyrrole derivatives that were assayed for their in vitro inhibitory effects toward COX isozymes. Among them, the ethyl-2-methyl-5-[4-(methylsulfonyl)phenyl]-1-[3-fluorophenyl]-1H-pyrrol-3-acetate (1d), which was the most potent and COX-2 selective compound, also showed a very interesting in vivo anti-inflammatory and analgesic activity, laying the foundations for developing new lead compounds that could be effective agents in the armamentarium for the management of inflammation and pain.
• Novel Analgesic/Anti-Inflammatory Agents: Diarylpyrrole Acetic Esters Endowed with Nitric Oxide Releasing Properties
  作者：Mariangela Biava、Giulio Cesare Porretta、Giovanna Poce、Claudio Battilocchio、Salvatore Alfonso、Michele Rovini、Salvatore Valenti、Gianluca Giorgi、Vincenzo Calderone、Alma Martelli、Lara Testai、Lidia Sautebin、Antonietta Rossi、Giuseppina Papa、Carla Ghelardini、Lorenzo Di Cesare Mannelli、Antonio Giordani、Paola Anzellotti、Annalisa Bruno、Paola Patrignani、Maurizio Anzini

  DOI：10.1021/jm200715n

  日期：2011.11.24

  The design of compounds that are able to inhibit cyclooxygenase (COX) and to release nitric oxide (NO) should give rise to drugs endowed with an overall safer profile for the gastrointestinal and cardiovascular systems. Herein we report a new class of pyrrole-derived nitrooxy esters (11a-j), cyclooxygenase-2 (COX-2) selective inhibitors endowed with NO releasing properties, with the goal of generating new molecules able to both strongly inhibit this isoform and reduce the related adverse side effects. Taking into account the metabolic conversion of nitrooxy esters into corresponding alcohols, we also studied derivatives 12a-j. All compounds proved to be very potent and selective COX-2 inhibitors; nitrooxy derivatives displayed interesting ex vivo NO-dependent vasorelaxing properties. Compounds 11c, 11d, 12c, and 12d were selected for further in vivo studies that highlited good anti-inflammatory and antinociceptive activities. Finally, two selected compounds (11c and 12c) tested in human whole blood (HWB) assay proved to be preferential inhibitors of COX-2.
• A class of pyrrole derivatives endowed with analgesic/anti-inflammatory activity
  作者：Claudio Battilocchio、Giovanna Poce、Salvatore Alfonso、Giulio Cesare Porretta、Sara Consalvi、Lidia Sautebin、Simona Pace、Antonietta Rossi、Carla Ghelardini、Lorenzo Di Cesare Mannelli、Silvia Schenone、Antonio Giordani、Luigia Di Francesco、Paola Patrignani、Mariangela Biava

  DOI：10.1016/j.bmc.2013.04.031

  日期：2013.7

  We report the synthesis and bio-pharmacological evaluation of a class of pyrrole derivatives featuring a small appendage fragment (carbaldehyde, oxime, nitrile) on the central core. Compound 1c proved to be extremely effective in vivo, showing an interesting anti-nociceptic profile that is comparable to reference compounds already marketed, hence representing a great stimulus for a further improvement of this class of molecules. (C) 2013 Elsevier Ltd. All rights reserved.