6-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetamido)nicotinic acid

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二苯乙烯类
• 英文名称: 6-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetamido)nicotinic acid
• 英文别名: 6-[[2-[(3R,5R,6S)-1-[(1S)-2-tert-butylsulfonyl-1-cyclopropylethyl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetyl]amino]pyridine-3-carboxylic acid
• 化学式: C₃₅H₃₉Cl₂N₃O₆S
• 分子量: 700.683
• InChiKey: UQSDNKFAAYCQSH-KHRUNOBUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  47
• 可旋转键数：
  11
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  142
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  (3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-cyclopropyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium 4-methylbenzenesulfonate 在 sodium periodate 、 N-羟基-7-氮杂苯并三氮唑 、 ruthenium(III) trichloride hydrate 、 碳酸氢钠 、 1,2-二氯乙烷 、 lithium hydroxide 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 甲醇 、 水 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 26.0h， 生成 6-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetamido)nicotinic acid
  参考文献：
  名称：

  Discovery of AM-7209, a Potent and Selective 4-Amidobenzoic Acid Inhibitor of the MDM2–p53 Interaction

  摘要：

  Structure-based rational design and extensive structure-activity relationship studies led to the discovery of AMG 232 (1), a potent piperidinone inhibitor of the MDM2-p53 association, which is currently being evaluated in human clinical trials for the treatment of cancer. Further modifications of 1, including replacing the carboxylic acid with a 4-amidobenzoic acid, afforded AM-7209 (25), featuring improved potency (K-D from ITC competition was 38 pM, SJSA-1 EdU IC50 = 1.6 nM), remarkable pharmacokinetic properties, and in vivo antitumor activity in both the SJSA-1 osteosarcoma xenograft model (ED50 = 2.6 mg/kg QD) and the HCT-116 colorectal carcinoma xenograft model (ED50 = 10 mg/kg QD). In addition, 25 possesses distinct mechanisms of elimination compared to 1.

  DOI：

  10.1021/jm501550p

文献信息

• Discovery of AM-7209, a Potent and Selective 4-Amidobenzoic Acid Inhibitor of the MDM2–p53 Interaction
  作者：Yosup Rew、Daqing Sun、Xuelei Yan、Hilary P. Beck、Jude Canon、Ada Chen、Jason Duquette、John Eksterowicz、Brian M. Fox、Jiasheng Fu、Ana Z. Gonzalez、Jonathan Houze、Xin Huang、Min Jiang、Lixia Jin、Yihong Li、Zhihong Li、Yun Ling、Mei-Chu Lo、Alexander M. Long、Lawrence R. McGee、Joel McIntosh、Jonathan D. Oliner、Tao Osgood、Anne Y. Saiki、Paul Shaffer、Yu Chung Wang、Sarah Wortman、Peter Yakowec、Qiuping Ye、Dongyin Yu、Xiaoning Zhao、Jing Zhou、Julio C. Medina、Steven H. Olson

  DOI：10.1021/jm501550p

  日期：2014.12.26

  Structure-based rational design and extensive structure-activity relationship studies led to the discovery of AMG 232 (1), a potent piperidinone inhibitor of the MDM2-p53 association, which is currently being evaluated in human clinical trials for the treatment of cancer. Further modifications of 1, including replacing the carboxylic acid with a 4-amidobenzoic acid, afforded AM-7209 (25), featuring improved potency (K-D from ITC competition was 38 pM, SJSA-1 EdU IC50 = 1.6 nM), remarkable pharmacokinetic properties, and in vivo antitumor activity in both the SJSA-1 osteosarcoma xenograft model (ED50 = 2.6 mg/kg QD) and the HCT-116 colorectal carcinoma xenograft model (ED50 = 10 mg/kg QD). In addition, 25 possesses distinct mechanisms of elimination compared to 1.