(R)-5-(4-chlorophenyl)-4-(3-(4-(4-(4-((4-(dimethylamino)-1-(phenylthio)butan-2-yl)amino)-3-nitrophenylsulfonamido)-phenyl)piperazin-1-yl)phenyl)-N,1,2-trimethyl-1H-pyrrole-3-carboxamide | 1384512-97-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: (R)-5-(4-chlorophenyl)-4-(3-(4-(4-(4-((4-(dimethylamino)-1-(phenylthio)butan-2-yl)amino)-3-nitrophenylsulfonamido)-phenyl)piperazin-1-yl)phenyl)-N,1,2-trimethyl-1H-pyrrole-3-carboxamide
• 英文别名: 5-(4-chlorophenyl)-4-[3-[4-[4-[[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylamino]phenyl]piperazin-1-yl]phenyl]-N,1,2-trimethylpyrrole-3-carboxamide
• CAS: 1384512-97-3
• 化学式: C₄₈H₅₃ClN₈O₅S₂
• 分子量: 921.584
• InChiKey: YIWXRYUKSQGNMX-KXQOOQHDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  9.5
• 重原子数：
  64
• 可旋转键数：
  16
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  181
• 氢给体数：
  3
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  5-(4-氯苯基)-4-(3-碘苯基)-1,2-二甲基-1H-吡咯-3-羧酸乙酯 在 吡啶 、 copper(l) iodide 、 palladium 10% on activated carbon 、 氢气 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 、 L-脯氨酸 、 sodium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 乙醇 、 二氯甲烷 、 水 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 20.0 ℃ 、101.33 kPa 条件下， 反应 0.75h， 生成 (R)-5-(4-chlorophenyl)-4-(3-(4-(4-(4-((4-(dimethylamino)-1-(phenylthio)butan-2-yl)amino)-3-nitrophenylsulfonamido)-phenyl)piperazin-1-yl)phenyl)-N,1,2-trimethyl-1H-pyrrole-3-carboxamide
  参考文献：
  名称：

  A Potent and Highly Efficacious Bcl-2/Bcl-xL Inhibitor

  摘要：

  Our previously reported Bcl-2/Bcl-xL inhibitor, 4, effectively inhibited tumor growth but failed to achieve complete regression in vivo. We have now performed extensive modifications on its pyrrole core structure, which has culminated in the discovery of 32 (BM-1074). Compound 32 binds to Bcl-2 and Bcl-xL proteins with K-i values of <1 nM and inhibits cancer cell growth with IC50 values of 1-2 nM in four small-cell lung cancer cell lines sensitive to potent and specific Bcl-2/Bcl-xL inhibitors. Compound 32 is capable of achieving rapid, complete, and durable tumor regression in vivo at a well-tolerated dose schedule. Compound 32 is the most potent and efficacious Bcl-2/Bcl-xL inhibitor reported to date.

  DOI：

  10.1021/jm4001105

文献信息

• Structure-Based Design of Potent Bcl-2/Bcl-xL Inhibitors with Strong in Vivo Antitumor Activity
  作者：Haibin Zhou、Angelo Aguilar、Jianfang Chen、Longchuan Bai、Liu Liu、Jennifer L. Meagher、Chao-Yie Yang、Donna McEachern、Xin Cong、Jeanne A. Stuckey、Shaomeng Wang

  DOI：10.1021/jm300608w

  日期：2012.7.12

  Bcl-2 and Bcl-xL are key apoptosis regulators and attractive cancer therapeutic targets. We have designed and optimized a class of small-molecule inhibitors of Bcl-2 and Bcl-xL containing a 4,5-diphenyl-1H-pyrrole-3-carboxylic acid core structure. A 1.4 angstrom resolution crystal structure of a lead compound, 12, complexed with Bcl-xL has provided a basis for our optimization. The most potent compounds, 14 and 15, bind to Bcl-2 and Bcl-xL with subnanomolar K-i values and are potent antagonists of Bcl-2 and Bcl-xL in functional assays. Compounds 14 and 15 inhibit cell growth with low nanomolar IC50 values in multiple small-cell lung cancer cell lines and induce robust apoptosis in cancer cells at concentrations as low as 10 nM. Compound 14 also achieves strong antitumor activity in an animal model of human cancer.
• 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.
• A Potent and Highly Efficacious Bcl-2/Bcl-xL Inhibitor
  作者：Angelo Aguilar、Haibin Zhou、Jianfang Chen、Liu Liu、Longchuan Bai、Donna McEachern、Chao-Yie Yang、Jennifer Meagher、Jeanne Stuckey、Shaomeng Wang

  DOI：10.1021/jm4001105

  日期：2013.4.11

  Our previously reported Bcl-2/Bcl-xL inhibitor, 4, effectively inhibited tumor growth but failed to achieve complete regression in vivo. We have now performed extensive modifications on its pyrrole core structure, which has culminated in the discovery of 32 (BM-1074). Compound 32 binds to Bcl-2 and Bcl-xL proteins with K-i values of <1 nM and inhibits cancer cell growth with IC50 values of 1-2 nM in four small-cell lung cancer cell lines sensitive to potent and specific Bcl-2/Bcl-xL inhibitors. Compound 32 is capable of achieving rapid, complete, and durable tumor regression in vivo at a well-tolerated dose schedule. Compound 32 is the most potent and efficacious Bcl-2/Bcl-xL inhibitor reported to date.