(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 | 1391107-78-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: (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
• 英文别名: 5-(4-chlorophenyl)-1,2-dimethyl-4-[3-[4-[4-[[4-[[(2R)-1-phenylsulfanyl-4-piperidin-1-ylbutan-2-yl]amino]-3-(trifluoromethylsulfonyl)phenyl]sulfonylamino]phenyl]piperazin-1-yl]phenyl]pyrrole-3-carboxylic acid
• CAS: 1391107-78-0
• 化学式: C₅₁H₅₄ClF₃N₆O₆S₃
• 分子量: 1035.67
• InChiKey: MWYHHIIMXQLLQG-RRHRGVEJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  9
• 重原子数：
  70
• 可旋转键数：
  17
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  186
• 氢给体数：
  3
• 氢受体数：
  15

反应信息

• 作为产物：
  描述：

  4-氟-3-(三氟甲基磺酰基)苯磺酰氯 在 palladium on activated charcoal 、 氢气 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 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

文献信息

• USE OF A HETEROCYCLIC BCL-2 INHIBITOR FOR REMOVING SENESCENT CELLS AND TREATING SENESCENCE-ASSOCIATED CONDITIONS
  申请人：Unity Biotechnology, Inc.

  公开号：US20170266211A1

  公开（公告）日：2017-09-21

  Disclosed herein are compounds that are effective for treatment of various disease states. Dosing includes both single administration and regimens of cycling dosages.
• Structure-Based Discovery of BM-957 as a Potent Small-Molecule Inhibitor of Bcl-2 and Bcl-xL Capable of Achieving Complete Tumor Regression
  作者：Jianfang Chen、Haibin Zhou、Angelo Aguilar、Liu Liu、Longchuan Bai、Donna McEachern、Chao-Yie Yang、Jennifer L. Meagher、Jeanne A. Stuckey、Shaomeng Wang

  DOI：10.1021/jm3010306

  日期：2012.10.11

  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.