(R)-N-(4-(4-(3-(2-(4-chlorophenyl)-1,5-dimethyl-1H-pyrrol-3-yl)phenyl)piperazin-1-yl)phenyl)-4-((4-(dimethylamino)-1-(phenylthio)butan-2-yl)amino)-3-nitrobenzenesulfonamide | 1384512-99-5

• 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)-N-(4-(4-(3-(2-(4-chlorophenyl)-1,5-dimethyl-1H-pyrrol-3-yl)phenyl)piperazin-1-yl)phenyl)-4-((4-(dimethylamino)-1-(phenylthio)butan-2-yl)amino)-3-nitrobenzenesulfonamide
• 英文别名: N-[4-[4-[3-[2-(4-chlorophenyl)-1,5-dimethylpyrrol-3-yl]phenyl]piperazin-1-yl]phenyl]-4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrobenzenesulfonamide
• CAS: 1384512-99-5
• 化学式: C₄₆H₅₀ClN₇O₄S₂
• 分子量: 864.533
• InChiKey: IUURYJVPFGWYCA-KXQOOQHDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  10.3
• 重原子数：
  60
• 可旋转键数：
  15
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  152
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  ethyl 2-acetyl-4-(4-chlorophenyl)-3-(3-iodophenyl)-4-oxobutanoate 在 吡啶 、 copper(l) iodide 、 palladium 10% on activated carbon 、 氢气 、 N,N-二异丙基乙胺 、 三氟乙酸 、 L-脯氨酸 、 sodium hydroxide 作用下， 以 1,4-二氧六环 、 甲醇 、 乙醇 、 水 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 25.0h， 生成 (R)-N-(4-(4-(3-(2-(4-chlorophenyl)-1,5-dimethyl-1H-pyrrol-3-yl)phenyl)piperazin-1-yl)phenyl)-4-((4-(dimethylamino)-1-(phenylthio)butan-2-yl)amino)-3-nitrobenzenesulfonamide
  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

• BCL-2/BCL-XL INHIBITORS AND THERAPEUTIC METHODS USING THE SAME
  申请人：Wang Shaomeng

  公开号：US20120189539A1

  公开（公告）日：2012-07-26

  Inhibitors of Bcl-2/Bcl-xL and compositions containing the same are disclosed. Methods of using the Bcl-2/Bcl-xL inhibitors in the treatment of diseases and conditions wherein inhibition of Bcl-2/Bcl-xL provides a benefit, like cancers, also are disclosed.

  本文披露了Bcl-2/Bcl-xL抑制剂及其组合物。还披露了使用Bcl-2/Bcl-xL抑制剂治疗疾病和病况的方法，其中抑制Bcl-2/Bcl-xL会带来益处，例如癌症等。
• BCL-2/BCL-XL INHIBITORS FOR USE IN THE TREATMENT OF CANCER
  申请人：The Regents of The University of Michigan

  公开号：EP2668180B1

  公开（公告）日：2018-08-01
• 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.
• [EN] BCL-2/BCL-XL INHIBITORS AND THERAPEUTIC METHODS USING THE SAME<br/>[FR] INHIBITEURS DE BCL-2/BCL-XL ET MÉTHODES THÉRAPEUTIQUES LES UTILISANT
  申请人：UNIV MICHIGAN

  公开号：WO2012103059A2

  公开（公告）日：2012-08-02

  Inhibitors of Bcl-2/Bcl-xL and compositions containing the same are disclosed. Methods of using the Bcl-2/Bcl-xL inhibitors in the treatment of diseases and conditions wherein inhibition of Bcl-2/Bcl-xL provides a benefit, like cancers, also are disclosed.