5-(4-chlorophenyl)-4-(3-(4-(4-(4-fluoro-3-(trifluoromethylsulfonyl)phenylsulfonamido)phenyl)piperazin-1-yl)-phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxylic acid | 1402141-65-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: 5-(4-chlorophenyl)-4-(3-(4-(4-(4-fluoro-3-(trifluoromethylsulfonyl)phenylsulfonamido)phenyl)piperazin-1-yl)-phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxylic acid
• 英文别名: 5-(4-Chlorophenyl)-4-[3-[4-[4-[[4-fluoro-3-(trifluoromethylsulfonyl)phenyl]sulfonylamino]phenyl]piperazin-1-yl]phenyl]-1,2-dimethylpyrrole-3-carboxylic acid；5-(4-chlorophenyl)-4-[3-[4-[4-[[4-fluoro-3-(trifluoromethylsulfonyl)phenyl]sulfonylamino]phenyl]piperazin-1-yl]phenyl]-1,2-dimethylpyrrole-3-carboxylic acid
• CAS: 1402141-65-4
• 化学式: C₃₆H₃₁ClF₄N₄O₆S₂
• 分子量: 791.244
• InChiKey: JAKWZENVQBHFNL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.3
• 重原子数：
  53
• 可旋转键数：
  9
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  146
• 氢给体数：
  2
• 氢受体数：
  13

反应信息

• 作为反应物：
  描述：

  (R)-1-(phenylthio)-4-(piperidin-1-yl)butan-2-amine 、 5-(4-chlorophenyl)-4-(3-(4-(4-(4-fluoro-3-(trifluoromethylsulfonyl)phenylsulfonamido)phenyl)piperazin-1-yl)-phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxylic acid 在 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 (R)-5-(4-chlorophenyl)-1,2-dimethyl-4-(3-(4-(4-(4-(1-(phenylthio)-4-(piperidin-1-yl)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonamido)phenyl)piperazin-1-yl)-phenyl)-1H-pyrrole-3-carboxylic acid
  参考文献：
  名称：

  Structure-Based Discovery of BM-957 as a Potent Small-Molecule Inhibitor of Bcl-2 and Bcl-xL Capable of Achieving Complete Tumor Regression

  摘要：

  Bcl-2 and Bcl-xL antiapoptotic proteins are attractive cancer therapeutic targets. We have previously reported the design of 4,5-diphenyl-1H-pyrrole-3-carboxylic acids as a class of potent Bcl-2/Bcl-xL inhibitors. In the present study, we report our structure-based optimization for this class of compounds based upon the crystal structure of Bcl-xL complexed with a potent lead compound. Our efforts accumulated into the design of compound 30 (BM-957), which binds to Bcl-2 and Bcl-xL with K-i < 1 nM and has low nanomolar IC50 values in cell growth inhibition in cancer cell lines. Significantly, compound 30 achieves rapid, complete, and durable tumor regression in the H146 small-cell lung cancer xenograft model at a well-tolerated dose schedule.

  DOI：

  10.1021/jm3010306
• 作为产物：
  描述：

  4-氟-3-(三氟甲基磺酰基)苯磺酰氯 、 5-(4-chlorophenyl)-1,2-dimethyl-4-(3-(4-(4-nitrophenyl)-piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid 在 palladium on activated charcoal 、 氢气 、 吡啶 、 苯胺 作用下， 以 甲醇 为溶剂， 生成 5-(4-chlorophenyl)-4-(3-(4-(4-(4-fluoro-3-(trifluoromethylsulfonyl)phenylsulfonamido)phenyl)piperazin-1-yl)-phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxylic acid
  参考文献：
  名称：

  Structure-Based Discovery of BM-957 as a Potent Small-Molecule Inhibitor of Bcl-2 and Bcl-xL Capable of Achieving Complete Tumor Regression

  摘要：

  Bcl-2 and Bcl-xL antiapoptotic proteins are attractive cancer therapeutic targets. We have previously reported the design of 4,5-diphenyl-1H-pyrrole-3-carboxylic acids as a class of potent Bcl-2/Bcl-xL inhibitors. In the present study, we report our structure-based optimization for this class of compounds based upon the crystal structure of Bcl-xL complexed with a potent lead compound. Our efforts accumulated into the design of compound 30 (BM-957), which binds to Bcl-2 and Bcl-xL with K-i < 1 nM and has low nanomolar IC50 values in cell growth inhibition in cancer cell lines. Significantly, compound 30 achieves rapid, complete, and durable tumor regression in the H146 small-cell lung cancer xenograft model at a well-tolerated dose schedule.

  DOI：

  10.1021/jm3010306