3,5-bis(4-methoxyphenyl)-4-(4-N-piperidinylbutyl)-1-phenyl-1H-pyrazole | 263717-74-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 3,5-bis(4-methoxyphenyl)-4-(4-N-piperidinylbutyl)-1-phenyl-1H-pyrazole
• CAS: 263717-74-4
• 化学式: C₃₂H₃₇N₃O₂
• 分子量: 495.665
• InChiKey: HRUGAQHPULFBRA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.03
• 重原子数：
  37.0
• 可旋转键数：
  10.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.34
• 拓扑面积：
  39.52
• 氢给体数：
  0.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  3,5-bis(4-methoxyphenyl)-4-(4-N-piperidinylbutyl)-1-phenyl-1H-pyrazole 在 三氯化铝 、 乙硫醇 作用下， 以 二氯甲烷 为溶剂， 反应 0.5h， 以54%的产率得到4-(4-N-piperidinylbutyl)-3,5-di-(4-hydroxyphenyl)-1-phenylpyrazole hydrochloride
  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：

  6-溴己酰氯 在 三氯化铝 、 四甲基乙二胺 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 27.0h， 生成 3,5-bis(4-methoxyphenyl)-4-(4-N-piperidinylbutyl)-1-phenyl-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