1-[4-(2-N-piperidinyl-ethoxy)-phenyl]-3,5-bis(4-methoxyphenyl)-4-ethyl-1H-pyrazole | 263717-71-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 1-[4-(2-N-piperidinyl-ethoxy)-phenyl]-3,5-bis(4-methoxyphenyl)-4-ethyl-1H-pyrazole
• 英文别名: 1-[2-[4-[4-Ethyl-3,5-bis(4-methoxyphenyl)pyrazol-1-yl]phenoxy]ethyl]piperidine
• CAS: 263717-71-1
• 化学式: C₃₂H₃₇N₃O₃
• 分子量: 511.664
• InChiKey: BYXPUTBGKWSZEF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.8
• 重原子数：
  38
• 可旋转键数：
  10
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.34
• 拓扑面积：
  48.8
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-[4-(2-N-piperidinyl-ethoxy)-phenyl]-3,5-bis(4-methoxyphenyl)-4-ethyl-1H-pyrazole 在 三溴化硼 作用下， 以 二氯甲烷 为溶剂， 反应 4.0h， 以75%的产率得到4-[4-Ethyl-5-(4-hydroxyphenyl)-2-[4-(2-piperidin-1-ylethoxy)phenyl]pyrazol-3-yl]phenol
  参考文献：
  名称：

  Triarylpyrazoles with basic side chains

  摘要：

  Recently, we developed a novel triaryl-substituted pyrazole ligand system that has high affinity for the estrogen receptor (ER) (Fink, B. E.; Mortenson, D. S.; Stauffer, S. R.; Aron, Z. D.; Katzenellenbogen, J. A. Chem. Biol. 1999, 6, 205). Subsequent work has shown that some analogues in this series are very selective for the ERT alpha. subtype in terms of binding affinity and agonist potency (Stauffer, S. R.; Coletta, C. J.; Tedesco, R.; Sun, J.; Katzenellenbogen, J. A. J. Med. Chem. 2000, submitted). We now investigate how this pyrazole ER agonist system might be converted into an antagonist or a selective estrogen receptor modifier (SERM) by incorporating a basic or polar side chain like those typically found in antiestrogens and known to be essential determinants of their mixed agonist/antagonist character. We selected an N-piperidinyl-ethyl chain as a first attempt, and introduced it at the four possible sites of substitution on the pyrazole core structure to determine the orientation that the pyrazole might adopt in the ER ligand binding pocket. Of these four, the C(5) piperidinyl-ethoxy-substituted pyrazole 5 had by far the highest affinity. Also, it bound to the ER subtype alpha (ER alpha) with 20-fold higher affinity than to ERP. In cell-based transcription assays, pyrazole 5 was an antagonist on both ER alpha and ER beta, and it was also more potent on ER alpha. Based on structure-binding affinity relationships and on molecular modeling studies of these pyrazoles in a crystal structure of the ER alpha -raloxifene complex, we propose that pyrazoles having a basic substituent on the C(5) phenyl group adopt a binding mode that is different from that of the pyrazole agonists that lack this group. The most favorable orientation appears to be one which places the N(1) phenol in the A-ring binding pocket so that the basic side chain can adopt an orientation similar to that of the basic side chain of raloxifene. (CV) 2000 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(00)00226-1
• 作为产物：
  描述：

  1-(2-(4-溴苯氧基)乙基)哌啶 在 正丁基锂 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 5.67h， 生成 1-[4-(2-N-piperidinyl-ethoxy)-phenyl]-3,5-bis(4-methoxyphenyl)-4-ethyl-1H-pyrazole
  参考文献：
  名称：

  Triarylpyrazoles with basic side chains

  摘要：

  Recently, we developed a novel triaryl-substituted pyrazole ligand system that has high affinity for the estrogen receptor (ER) (Fink, B. E.; Mortenson, D. S.; Stauffer, S. R.; Aron, Z. D.; Katzenellenbogen, J. A. Chem. Biol. 1999, 6, 205). Subsequent work has shown that some analogues in this series are very selective for the ERT alpha. subtype in terms of binding affinity and agonist potency (Stauffer, S. R.; Coletta, C. J.; Tedesco, R.; Sun, J.; Katzenellenbogen, J. A. J. Med. Chem. 2000, submitted). We now investigate how this pyrazole ER agonist system might be converted into an antagonist or a selective estrogen receptor modifier (SERM) by incorporating a basic or polar side chain like those typically found in antiestrogens and known to be essential determinants of their mixed agonist/antagonist character. We selected an N-piperidinyl-ethyl chain as a first attempt, and introduced it at the four possible sites of substitution on the pyrazole core structure to determine the orientation that the pyrazole might adopt in the ER ligand binding pocket. Of these four, the C(5) piperidinyl-ethoxy-substituted pyrazole 5 had by far the highest affinity. Also, it bound to the ER subtype alpha (ER alpha) with 20-fold higher affinity than to ERP. In cell-based transcription assays, pyrazole 5 was an antagonist on both ER alpha and ER beta, and it was also more potent on ER alpha. Based on structure-binding affinity relationships and on molecular modeling studies of these pyrazoles in a crystal structure of the ER alpha -raloxifene complex, we propose that pyrazoles having a basic substituent on the C(5) phenyl group adopt a binding mode that is different from that of the pyrazole agonists that lack this group. The most favorable orientation appears to be one which places the N(1) phenol in the A-ring binding pocket so that the basic side chain can adopt an orientation similar to that of the basic side chain of raloxifene. (CV) 2000 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(00)00226-1

文献信息

• [EN] TOLL-LIKE RECEPTOR SIGNALING INHIBITORS<br/>[FR] INHIBITEURS DE SIGNALISATION DE RÉCEPTEUR DE TYPE TOLL
  申请人：UNIV ILLINOIS

  公开号：WO2019136147A1

  公开（公告）日：2019-07-11

  Di- and triaryl-substituted heteroaromatic compounds have Toll-like receptor inhibitory activity, including at TLR2, TLR4, TLR7, and/or TLR9. Compounds and compositions have applications in the treatment of diseases and conditions mediated by Toll-like receptors and related receptors, such as bacterial sepsis, autoimmune disease, lupus erythematosus, ischemia-reperfusion injury, stroke, metabolic disease, obesity-related metabolic inflammation, gout, and cancer.

  二芳基和三芳基取代的杂环化合物具有Toll样受体抑制活性，包括在TLR2、TLR4、TLR7和/或TLR9上。这些化合物和组合物在治疗由Toll样受体和相关受体介导的疾病和症状方面具有应用，如细菌性败血症、自身免疫疾病、红斑狼疮、缺血再灌注损伤、中风、代谢疾病、与肥胖相关的代谢性炎症、痛风和癌症。
• WO2007/98090
  申请人：——

  公开号：——

  公开（公告）日：——