(R)-4-(4-(dimethylamino)-1-(phenylthio)butan-2-ylamino)-3-(2,2,2-trifluoroacetyl)benzenesulfonamide | 1065603-86-2

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (R)-4-(4-(dimethylamino)-1-(phenylthio)butan-2-ylamino)-3-(2,2,2-trifluoroacetyl)benzenesulfonamide
• 英文别名: 4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-(2,2,2-trifluoroacetyl)benzenesulfonamide
• CAS: 1065603-86-2
• 化学式: C₂₀H₂₄F₃N₃O₃S₂
• 分子量: 475.556
• InChiKey: LETQUZZNDOVFBJ-CQSZACIVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  31
• 可旋转键数：
  10
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  126
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  4-[4-(4'-氯联苯-2-基甲基)哌嗪-1-基]苯甲酸 、 (R)-4-(4-(dimethylamino)-1-(phenylthio)butan-2-ylamino)-3-(2,2,2-trifluoroacetyl)benzenesulfonamide 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 15.0h， 生成 (R)-4-(-4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-N-(4-(4-(dimethylamino)-1-(phenylthio)butan-2-ylamino)-3-(2,2,2-trifluoroacetyl)phenylsulfonyl)benzamide
  参考文献：
  名称：

  Discovery of an Orally Bioavailable Small Molecule Inhibitor of Prosurvival B-Cell Lymphoma 2 Proteins

  摘要：

  Overexpression of prosurvival proteins such as Bcl-2 and Bcl-X-L has been correlated with tumorigenesis and resistance to chemotherapy, and thus, the development of antagonists of these proteins may provide a novel means for the treatment of cancer. We recently described the discovery of 1 (ABT-737), which binds Bcl-2, Bcl-X-L, and Bcl-w with high affinity, shows robust antitumor activity in murine tumor xenograft models, but is not orally bioavailable. Herein, we report that targeted modifications at three key positions of 1 resulted in a 20-fold improvement in the pharmacokinetic/pharmacodynamic relationship (PK/PD) between oral exposure (AUC) and in vitro efficacy in human tumor cell lines (EC50). The resulting compound, 2 (ABT-263), is orally efficacious in an established xenograft model of human small cell lung cancer, inducing complete tumor regressions in all animals. Compound 2 is currently in multiple phase 1 clinical trials in patients with small cell lung cancer and hematological malignancies.

  DOI：

  10.1021/jm800669s
• 作为产物：
  描述：

  (R)-N¹,N¹-dimethyl-4-(phenylthio)butane-1,3-diamine 、 4-fluoro-3-(2,2,2-trifluoro-1,1-dihydroxyethyl)benzenesulfonamide 在 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 为溶剂， 生成 (R)-4-(4-(dimethylamino)-1-(phenylthio)butan-2-ylamino)-3-(2,2,2-trifluoroacetyl)benzenesulfonamide
  参考文献：
  名称：

  Discovery of an Orally Bioavailable Small Molecule Inhibitor of Prosurvival B-Cell Lymphoma 2 Proteins

  摘要：

  Overexpression of prosurvival proteins such as Bcl-2 and Bcl-X-L has been correlated with tumorigenesis and resistance to chemotherapy, and thus, the development of antagonists of these proteins may provide a novel means for the treatment of cancer. We recently described the discovery of 1 (ABT-737), which binds Bcl-2, Bcl-X-L, and Bcl-w with high affinity, shows robust antitumor activity in murine tumor xenograft models, but is not orally bioavailable. Herein, we report that targeted modifications at three key positions of 1 resulted in a 20-fold improvement in the pharmacokinetic/pharmacodynamic relationship (PK/PD) between oral exposure (AUC) and in vitro efficacy in human tumor cell lines (EC50). The resulting compound, 2 (ABT-263), is orally efficacious in an established xenograft model of human small cell lung cancer, inducing complete tumor regressions in all animals. Compound 2 is currently in multiple phase 1 clinical trials in patients with small cell lung cancer and hematological malignancies.

  DOI：

  10.1021/jm800669s

文献信息

• Discovery of an Orally Bioavailable Small Molecule Inhibitor of Prosurvival B-Cell Lymphoma 2 Proteins
  作者：Cheol-Min Park、Milan Bruncko、Jessica Adickes、Joy Bauch、Hong Ding、Aaron Kunzer、Kennan C. Marsh、Paul Nimmer、Alexander R. Shoemaker、Xiaohong Song、Stephen K. Tahir、Christin Tse、Xilu Wang、Michael D. Wendt、Xiufen Yang、Haichao Zhang、Stephen W. Fesik、Saul H. Rosenberg、Steven W. Elmore

  DOI：10.1021/jm800669s

  日期：2008.11.13

  Overexpression of prosurvival proteins such as Bcl-2 and Bcl-X-L has been correlated with tumorigenesis and resistance to chemotherapy, and thus, the development of antagonists of these proteins may provide a novel means for the treatment of cancer. We recently described the discovery of 1 (ABT-737), which binds Bcl-2, Bcl-X-L, and Bcl-w with high affinity, shows robust antitumor activity in murine tumor xenograft models, but is not orally bioavailable. Herein, we report that targeted modifications at three key positions of 1 resulted in a 20-fold improvement in the pharmacokinetic/pharmacodynamic relationship (PK/PD) between oral exposure (AUC) and in vitro efficacy in human tumor cell lines (EC50). The resulting compound, 2 (ABT-263), is orally efficacious in an established xenograft model of human small cell lung cancer, inducing complete tumor regressions in all animals. Compound 2 is currently in multiple phase 1 clinical trials in patients with small cell lung cancer and hematological malignancies.