(3S)-3-(4-aminophenyl)piperidinium (2R,3R)-3-carboxy-2,3-dihydroxypropanoate | 1196713-22-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: (3S)-3-(4-aminophenyl)piperidinium (2R,3R)-3-carboxy-2,3-dihydroxypropanoate
• 英文别名: (2R,3R)-2,3-dihydroxybutanedioic acid;4-[(3S)-piperidin-3-yl]aniline
• CAS: 1196713-22-0
• 化学式: C₄H₆O₆*C₁₁H₁₆N₂
• 分子量: 326.349
• InChiKey: UPDIVAQERFSQBY-PRCBPEIBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.39
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  153
• 氢给体数：
  6
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  二碳酸二叔丁酯 、 (3S)-3-(4-aminophenyl)piperidinium (2R,3R)-3-carboxy-2,3-dihydroxypropanoate 在 氨 作用下， 以 甲醇 、 二氯甲烷 、 水 为溶剂， 反应 1.17h， 以92%的产率得到tert-butyl (S)-3-(4-aminophenyl)piperidine-1-carboxylate
  参考文献：
  名称：

  Discovery of 2-{4-[(3S)-Piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): A Novel Oral Poly(ADP-ribose)polymerase (PARP) Inhibitor Efficacious in BRCA-1 and -2 Mutant Tumors

  摘要：

  We disclose the development of a novel series of 2-phenyl-2H-indazole-7-carboxamides as poly(ADPribose)polymerase (PARP) 1 and 2 inhibitors. This series was optimized to improve enzyme and cellular activity, and the resulting PARP inhibitors display antiproliferation activities against BRCA-1 and BRCA-2 deficient cancer cells, with high selectivity over BRCA proficient cells. Extrahepatic oxidation by CYP450 1A1 and 1A2 was identified as a metabolic concern, and strategies to improve pharmacokinetic properties are reported. These efforts culminated in the identification of 2-{4-[(3S)-piperidin-3yl]phenyl}-2H-indazole-7-carboxamide 56 (MK-4827), which displays good pharmacokinetic properties and is currently in phase I clinical trials. This compound displays excellent PARP 1 and 2 inhibition with IC50 = 3.8 and 2.1 nM, respectively, and in a whole cell assay, it inhibited PARP activity with EC50 = 4 nM and inhibited proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC50 in the 10-100 nM range. Compound 56 was well tolerated in vivo and demonstrated efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer.

  DOI：

  10.1021/jm901188v
• 作为产物：
  描述：

  L-酒石酸 、 4-(哌啶-3-基)苯胺 以 乙醇 为溶剂， 以24.8%的产率得到(3S)-3-(4-aminophenyl)piperidinium (2R,3R)-3-carboxy-2,3-dihydroxypropanoate
  参考文献：
  名称：

  Discovery of 2-{4-[(3S)-Piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): A Novel Oral Poly(ADP-ribose)polymerase (PARP) Inhibitor Efficacious in BRCA-1 and -2 Mutant Tumors

  摘要：

  We disclose the development of a novel series of 2-phenyl-2H-indazole-7-carboxamides as poly(ADPribose)polymerase (PARP) 1 and 2 inhibitors. This series was optimized to improve enzyme and cellular activity, and the resulting PARP inhibitors display antiproliferation activities against BRCA-1 and BRCA-2 deficient cancer cells, with high selectivity over BRCA proficient cells. Extrahepatic oxidation by CYP450 1A1 and 1A2 was identified as a metabolic concern, and strategies to improve pharmacokinetic properties are reported. These efforts culminated in the identification of 2-{4-[(3S)-piperidin-3yl]phenyl}-2H-indazole-7-carboxamide 56 (MK-4827), which displays good pharmacokinetic properties and is currently in phase I clinical trials. This compound displays excellent PARP 1 and 2 inhibition with IC50 = 3.8 and 2.1 nM, respectively, and in a whole cell assay, it inhibited PARP activity with EC50 = 4 nM and inhibited proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC50 in the 10-100 nM range. Compound 56 was well tolerated in vivo and demonstrated efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer.

  DOI：

  10.1021/jm901188v

文献信息

• Discovery of 2-{4-[(3<i>S</i>)-Piperidin-3-yl]phenyl}-2<i>H</i>-indazole-7-carboxamide (MK-4827): A Novel Oral Poly(ADP-ribose)polymerase (PARP) Inhibitor Efficacious in BRCA-1 and -2 Mutant Tumors
  作者：Philip Jones、Sergio Altamura、Julia Boueres、Federica Ferrigno、Massimiliano Fonsi、Claudia Giomini、Stefania Lamartina、Edith Monteagudo、Jesus M. Ontoria、Maria Vittoria Orsale、Maria Cecilia Palumbi、Silvia Pesci、Giuseppe Roscilli、Rita Scarpelli、Carsten Schultz-Fademrecht、Carlo Toniatti、Michael Rowley

  DOI：10.1021/jm901188v

  日期：2009.11.26

  We disclose the development of a novel series of 2-phenyl-2H-indazole-7-carboxamides as poly(ADPribose)polymerase (PARP) 1 and 2 inhibitors. This series was optimized to improve enzyme and cellular activity, and the resulting PARP inhibitors display antiproliferation activities against BRCA-1 and BRCA-2 deficient cancer cells, with high selectivity over BRCA proficient cells. Extrahepatic oxidation by CYP450 1A1 and 1A2 was identified as a metabolic concern, and strategies to improve pharmacokinetic properties are reported. These efforts culminated in the identification of 2-4-[(3S)-piperidin-3yl]phenyl}-2H-indazole-7-carboxamide 56 (MK-4827), which displays good pharmacokinetic properties and is currently in phase I clinical trials. This compound displays excellent PARP 1 and 2 inhibition with IC50 = 3.8 and 2.1 nM, respectively, and in a whole cell assay, it inhibited PARP activity with EC50 = 4 nM and inhibited proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC50 in the 10-100 nM range. Compound 56 was well tolerated in vivo and demonstrated efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer.