(R)-(9H-fluoren-9-yl)methyl 4-(azetidin-1-yl)-4-oxo-1-(phenylthio)butan-2-yl carbamate | 1402141-81-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 芴
• 英文名称: (R)-(9H-fluoren-9-yl)methyl 4-(azetidin-1-yl)-4-oxo-1-(phenylthio)butan-2-yl carbamate
• 英文别名: 9H-fluoren-9-ylmethyl N-[(2R)-4-(azetidin-1-yl)-4-oxo-1-phenylsulfanylbutan-2-yl]carbamate
• CAS: 1402141-81-4
• 化学式: C₂₈H₂₈N₂O₃S
• 分子量: 472.608
• InChiKey: ODQXNFTVSIIWFM-HXUWFJFHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  34
• 可旋转键数：
  9
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  83.9
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (R)-(9H-fluoren-9-yl)methyl 4-(azetidin-1-yl)-4-oxo-1-(phenylthio)butan-2-yl carbamate 在 二乙胺 作用下， 以 乙腈 为溶剂， 反应 2.0h， 以98%的产率得到(R)-3-amino-1-(azetidin-1-yl)-4-(phenylthio)butan-1-one
  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：

  杂氮环丁烷 、 (R)-N-Fmoc-3-氨基-4-(苯硫基)丁酸 在 1-羟基苯并三唑 、 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 4.0h， 以88%的产率得到(R)-(9H-fluoren-9-yl)methyl 4-(azetidin-1-yl)-4-oxo-1-(phenylthio)butan-2-yl carbamate
  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

• 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.