5-(4-chlorophenyl)-1,2-dimethyl-N-(3-(4-methylpiperazin-1-yl)-propyl)-4-(3-(4-(4-nitrophenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxamide | 1402141-64-3

• 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)-1,2-dimethyl-N-(3-(4-methylpiperazin-1-yl)-propyl)-4-(3-(4-(4-nitrophenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxamide
• 英文别名: 5-(4-chlorophenyl)-1,2-dimethyl-N-[3-(4-methylpiperazin-1-yl)propyl]-4-[3-[4-(4-nitrophenyl)piperazin-1-yl]phenyl]pyrrole-3-carboxamide
• CAS: 1402141-64-3
• 化学式: C₃₇H₄₄ClN₇O₃
• 分子量: 670.254
• InChiKey: SNAYZQRNWMVAIR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6
• 重原子数：
  48
• 可旋转键数：
  9
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  92.8
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  5-(4-chlorophenyl)-1,2-dimethyl-N-(3-(4-methylpiperazin-1-yl)-propyl)-4-(3-(4-(4-nitrophenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxamide 在 吡啶 、 palladium on activated charcoal 、 氢气 、 苯胺 作用下， 以 甲醇 为溶剂， 反应 0.33h， 生成 5-(4-chlorophenyl)-1,2-dimethyl-N-(3-(4-methylpiperazin-1-yl)propyl)-4-(3-(4-(4-(3-methylphenylsulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxamide
  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：

  1-(3-氨丙基)-4-甲基哌嗪 、 5-(4-chlorophenyl)-1,2-dimethyl-4-(3-(4-(4-nitrophenyl)-piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid 在 4-二甲氨基吡啶 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 以86%的产率得到5-(4-chlorophenyl)-1,2-dimethyl-N-(3-(4-methylpiperazin-1-yl)-propyl)-4-(3-(4-(4-nitrophenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxamide
  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