4-(4-aminomethylphenyl)-5-(2,4-bis-benzyloxy-5-chlorophenyl)-2H-pyrazole-3-carboxylic acid ethylamide | 1001385-52-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 4-(4-aminomethylphenyl)-5-(2,4-bis-benzyloxy-5-chlorophenyl)-2H-pyrazole-3-carboxylic acid ethylamide
• 英文别名: 4-[4-(aminomethyl)phenyl]-3-[5-chloro-2,4-bis(phenylmethoxy)phenyl]-N-ethyl-1H-pyrazole-5-carboxamide
• CAS: 1001385-52-9
• 化学式: C₃₃H₃₁ClN₄O₃
• 分子量: 567.087
• InChiKey: QUUUJFFBMVTDNW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.9
• 重原子数：
  41
• 可旋转键数：
  11
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  102
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  二乙烯基砜 、 4-(4-aminomethylphenyl)-5-(2,4-bis-benzyloxy-5-chlorophenyl)-2H-pyrazole-3-carboxylic acid ethylamide 在 三乙胺 作用下， 以 乙醇 为溶剂， 反应 1.0h， 生成
  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：

  {4-[3-(2,4-bis(benzyloxy)-5-chlorophenyl)-5-ethylcarbamoyl-1H-pyrazol-4-yl]benzyl}carbamic acid tert-butyl ester 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 以95%的产率得到4-(4-aminomethylphenyl)-5-(2,4-bis-benzyloxy-5-chlorophenyl)-2H-pyrazole-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

• 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%.