5-{2,4-bis-benzyloxy-5-[2-(4-fluoro-phenyl)-ethyl]-phenyl}-isoxazole-3-carboxylic acid ethylamide | 1001385-77-8

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二苯乙烯类
• 英文名称: 5-{2,4-bis-benzyloxy-5-[2-(4-fluoro-phenyl)-ethyl]-phenyl}-isoxazole-3-carboxylic acid ethylamide
• 英文别名: N-ethyl-5-[5-[2-(4-fluorophenyl)ethyl]-2,4-bis(phenylmethoxy)phenyl]-1,2-oxazole-3-carboxamide
• CAS: 1001385-77-8
• 化学式: C₃₄H₃₁FN₂O₄
• 分子量: 550.63
• InChiKey: PREXWYCGWBWXPT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.3
• 重原子数：
  41
• 可旋转键数：
  12
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  73.6
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  5-{2,4-bis-benzyloxy-5-[2-(4-fluoro-phenyl)-ethyl]-phenyl}-isoxazole-3-carboxylic acid ethylamide 在 N-溴代丁二酰亚胺(NBS) 、 ammonium cerium(IV) nitrate 作用下， 以 乙腈 为溶剂， 反应 0.5h， 以59%的产率得到5-{2,4-bis(benzyloxy)-5-[2-(4-fluoro-phenyl)-ethyl]-phenyl}-4-bromoisoxazole-3-carboxylic acid ethylamide
  参考文献：
  名称：

  4,5-Diarylisoxazole Hsp90 Chaperone Inhibitors: Potential Therapeutic Agents for the Treatment of Cancer

  摘要：

  Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential chemotherapeutic agents for cancer. Here, we describe the structure-based design, synthesis, structure-activity relationships and pharmacokinetics of potent small-molecule inhibitors of Hsp90 based on the 4,5-diarylisoxazole scaffold. Analogues from this series have high affinity for Hsp90, as measured in a fluorescence polarization (FP) competitive binding assay, and are active in cancer cell lines where they inhibit proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Compound 40f (VER-52296/NVP-AUY922) is potent in the Hsp90 FP binding assay (IC50 = 21 nM) and inhibits proliferation of various human cancer cell lines in vitro, with GI50 averaging 9 nM. Compound 40f is retained in tumors in vivo when administered i.p., as evaluated by cassette dosing in tumor-bearing mice. In a human colon cancer xenograft model, 40f inhibits tumor growth by approximately 50%.

  DOI：

  10.1021/jm701018h
• 作为产物：
  描述：

  5-{2,4-bis-benzyloxy-5-[2-(4-fluoro-phenyl)-vinyl]-phenyl}-isoxazole-3-carboxylic acid ethylamide 在 palladium on activated charcoal 氢气 作用下， 以 1,4-二氧六环 为溶剂， 反应 4.75h， 以99%的产率得到5-{2,4-bis-benzyloxy-5-[2-(4-fluoro-phenyl)-ethyl]-phenyl}-isoxazole-3-carboxylic acid ethylamide
  参考文献：
  名称：

  4,5-Diarylisoxazole Hsp90 Chaperone Inhibitors: Potential Therapeutic Agents for the Treatment of Cancer

  摘要：

  Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential chemotherapeutic agents for cancer. Here, we describe the structure-based design, synthesis, structure-activity relationships and pharmacokinetics of potent small-molecule inhibitors of Hsp90 based on the 4,5-diarylisoxazole scaffold. Analogues from this series have high affinity for Hsp90, as measured in a fluorescence polarization (FP) competitive binding assay, and are active in cancer cell lines where they inhibit proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Compound 40f (VER-52296/NVP-AUY922) is potent in the Hsp90 FP binding assay (IC50 = 21 nM) and inhibits proliferation of various human cancer cell lines in vitro, with GI50 averaging 9 nM. Compound 40f is retained in tumors in vivo when administered i.p., as evaluated by cassette dosing in tumor-bearing mice. In a human colon cancer xenograft model, 40f inhibits tumor growth by approximately 50%.

  DOI：

  10.1021/jm701018h

文献信息

• [EN] RESORCINOL DERIVATIVES AS HSP90 INHIBITORS<br/>[FR] DÉRIVÉS DU RÉSORCINOL COMME INHIBITEURS DE LA HSP90
  申请人：NERVIANO MEDICAL SCIENCES SRL

  公开号：WO2010121963A1

  公开（公告）日：2010-10-28

  The present invention relates to substituted resorcinol derivatives which inhibit the activity of Heat Shock Protein HSP90. The compounds of the invention are therefore useful in treating proliferative diseases such as cancer and neurodegenerative diseases. The present invention also provides processes for preparing these compounds, pharmaceutical compositions comprising them, methods of treating diseases and the pharmaceutical compositions comprising these compounds.

  本发明涉及取代间苯二酚衍生物，这些衍生物抑制热休克蛋白HSP90的活性。因此，本发明的化合物可用于治疗诸如癌症和神经退行性疾病等增殖性疾病。本发明还提供了制备这些化合物的方法、包含它们的药物组合物、治疗疾病的方法以及包含这些化合物的药物组合物。
• RESORCINOL DERIVATIVES AS HSP90 INHIBITORS
  申请人：Brasca Maria Gabriella

  公开号：US20120046266A1

  公开（公告）日：2012-02-23

  The present invention relates to substituted resorcinol derivatives which inhibit the activity of Heat Shock Protein HSP90. The compounds of the invention are therefore useful in treating proliferative diseases such as cancer and neurodegenerative diseases. The present invention also provides processes for preparing these compounds, pharmaceutical compositions comprising them, methods of treating diseases and the pharmaceutical compositions comprising these compounds.

  本发明涉及替代苯醌衍生物，其抑制热休克蛋白HSP90的活性。因此，本发明的化合物在治疗增殖性疾病如癌症和神经退行性疾病方面有用。本发明还提供制备这些化合物的方法，包括它们的药物组合物，治疗疾病的方法以及包含这些化合物的药物组合物。
• US8993556B2
  申请人：——

  公开号：US8993556B2

  公开（公告）日：2015-03-31
• 4,5-Diarylisoxazole Hsp90 Chaperone Inhibitors: Potential Therapeutic Agents for the Treatment of Cancer
  作者：Paul A. Brough、Wynne Aherne、Xavier Barril、Jenifer Borgognoni、Kathy Boxall、Julie E. Cansfield、Kwai-Ming J. Cheung、Ian Collins、Nicholas G. M. Davies、Martin J. Drysdale、Brian Dymock、Suzanne A. Eccles、Harry Finch、Alexandra Fink、Angela Hayes、Robert Howes、Roderick E. Hubbard、Karen James、Allan M. Jordan、Andrea Lockie、Vanessa Martins、Andrew Massey、Thomas P. Matthews、Edward McDonald、Christopher J. Northfield、Laurence H. Pearl、Chrisostomos Prodromou、Stuart Ray、Florence I. Raynaud、Stephen D. Roughley、Swee Y. Sharp、Allan Surgenor、D. Lee Walmsley、Paul Webb、Mike Wood、Paul Workman、Lisa Wright

  DOI：10.1021/jm701018h

  日期：2008.1.1

  Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential chemotherapeutic agents for cancer. Here, we describe the structure-based design, synthesis, structure-activity relationships and pharmacokinetics of potent small-molecule inhibitors of Hsp90 based on the 4,5-diarylisoxazole scaffold. Analogues from this series have high affinity for Hsp90, as measured in a fluorescence polarization (FP) competitive binding assay, and are active in cancer cell lines where they inhibit proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Compound 40f (VER-52296/NVP-AUY922) is potent in the Hsp90 FP binding assay (IC50 = 21 nM) and inhibits proliferation of various human cancer cell lines in vitro, with GI50 averaging 9 nM. Compound 40f is retained in tumors in vivo when administered i.p., as evaluated by cassette dosing in tumor-bearing mice. In a human colon cancer xenograft model, 40f inhibits tumor growth by approximately 50%.