6-(4-fluoro-3-(4-(1-(pyrrolidin-1-yl)cyclopentanecarbonyl)piperazine-1-carbonyl)benzyl)-4,5-dimethylpyridazin-3(2H)-one | 1216936-19-4

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 6-(4-fluoro-3-(4-(1-(pyrrolidin-1-yl)cyclopentanecarbonyl)piperazine-1-carbonyl)benzyl)-4,5-dimethylpyridazin-3(2H)-one
• 英文别名: 3-[[4-fluoro-3-[4-(1-pyrrolidin-1-ylcyclopentanecarbonyl)piperazine-1-carbonyl]phenyl]methyl]-4,5-dimethyl-1H-pyridazin-6-one
• CAS: 1216936-19-4
• 化学式: C₂₈H₃₆FN₅O₃
• 分子量: 509.624
• InChiKey: RGBUEKBEKGTQBO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  37
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  85.3
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  6-[4-fluoro-3-(piperazin-1-ylcarbonyl)benzyl]-4,5-dimethylpyridazin-3(2H)-one 、 1-Pyrrolidin-1-ium-1-ylcyclopentane-1-carboxylate 在 1-羟基苯并三唑 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 6-(4-fluoro-3-(4-(1-(pyrrolidin-1-yl)cyclopentanecarbonyl)piperazine-1-carbonyl)benzyl)-4,5-dimethylpyridazin-3(2H)-one
  参考文献：
  名称：

  Development of substituted 6-[4-fluoro-3-(piperazin-1-ylcarbonyl)benzyl]-4,5-dimethylpyridazin-3(2H)-ones as potent poly(ADP–ribose) polymerase-1 (PARP-1) inhibitors active in BRCA deficient cells

  摘要：

  We describe an extensive SAR study in the 6-[4-fluoro-3-(substituted)benzyl]-4,5-dimethylpyridazin-3(2H)-one series which led to the identification of potent PARP-1 inhibitors, capable of inhibiting the proliferation of BRCA-1 deficient cancer cells in the low nanomolar range, and displaying >100-fold selectivity over the BRCA wild type counterparts. The series of compounds was devoid of hERG channel activity, and CYP inhibition and induction liabilities. Several analogs were stable in rat and human liver microsomes and displayed moderate rat clearance, with urinary excretion of parent as the major route of elimination. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2009.11.087

文献信息

• Development of substituted 6-[4-fluoro-3-(piperazin-1-ylcarbonyl)benzyl]-4,5-dimethylpyridazin-3(2H)-ones as potent poly(ADP–ribose) polymerase-1 (PARP-1) inhibitors active in BRCA deficient cells
  作者：Federica Ferrigno、Danila Branca、Olaf Kinzel、Samuele Lillini、Laura Llauger Bufi、Edith Monteagudo、Ester Muraglia、Michael Rowley、Carsten Schultz-Fademrecht、Carlo Toniatti、Caterina Torrisi、Philip Jones

  DOI：10.1016/j.bmcl.2009.11.087

  日期：2010.2

  We describe an extensive SAR study in the 6-[4-fluoro-3-(substituted)benzyl]-4,5-dimethylpyridazin-3(2H)-one series which led to the identification of potent PARP-1 inhibitors, capable of inhibiting the proliferation of BRCA-1 deficient cancer cells in the low nanomolar range, and displaying >100-fold selectivity over the BRCA wild type counterparts. The series of compounds was devoid of hERG channel activity, and CYP inhibition and induction liabilities. Several analogs were stable in rat and human liver microsomes and displayed moderate rat clearance, with urinary excretion of parent as the major route of elimination. (C) 2009 Elsevier Ltd. All rights reserved.