2-(2-(((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-chloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)methyl)thiazol-5-yl)-2,2-difluoroacetic acid | 1584731-69-0

• 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: 2-(2-(((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-chloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)methyl)thiazol-5-yl)-2,2-difluoroacetic acid
• 英文别名: 2-[2-[[(3R,5R,6S)-1-[(1S)-2-tert-butylsulfonyl-1-cyclopropylethyl]-6-(4-chloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]methyl]-1,3-thiazol-5-yl]-2,2-difluoroacetic acid
• CAS: 1584731-69-0
• 化学式: C₃₃H₃₅Cl₂F₃N₂O₅S₂
• 分子量: 731.685
• InChiKey: YMBUZVVHJGRMEZ-AJRUUFPASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.2
• 重原子数：
  47
• 可旋转键数：
  11
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  141
• 氢给体数：
  1
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  methyl 2-(2-(((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-chloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)methyl)thiazol-5-yl)acetate 在 sodium t-butanolate 、 N-氟代双苯磺酰胺 、 水 、 lithium hydroxide 作用下， 以 N,N-二甲基甲酰胺 、 四氢呋喃 、 甲醇 为溶剂， 反应 0.75h， 以12%的产率得到2-(2-(((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-chloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)methyl)thiazol-5-yl)-2-fluoroacetic acid
  参考文献：
  名称：

  Novel Inhibitors of the MDM2-p53 Interaction Featuring Hydrogen Bond Acceptors as Carboxylic Acid Isosteres

  摘要：

  We previously reported the discovery of potent and selective morpholinone and piperidinone inhibitors of the MDM2-p53 interaction. These inhibitors have in common a carboxylic acid moiety that engages in an electrostatic interaction with MDM2-His96. Our continued search for potent and diverse inhibitors led to the discovery of novel replacements for these acids uncovering new interactions with the MDM2 protein. In particular, using pyridine or thiazole as isosteres of the carboxylic acid moiety resulted in very potent analogues. From these, AM-6761 (4) emerged as a potent inhibitor with remarkable biochemical (HTRF IC50 = 0.1 nM) and cellular potency (SJSA-1 EdU IC50 = 16 nM), as well as favorable pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 11 mg/kg. Optimization efforts toward the discovery of these inhibitors as well as the new interactions observed with the MDM2 protein are described herein.

  DOI：

  10.1021/jm401911v

文献信息

• Novel Inhibitors of the MDM2-p53 Interaction Featuring Hydrogen Bond Acceptors as Carboxylic Acid Isosteres
  作者：Ana Z. Gonzalez、Zhihong Li、Hilary P. Beck、Jude Canon、Ada Chen、David Chow、Jason Duquette、John Eksterowicz、Brian M. Fox、Jiasheng Fu、Xin Huang、Jonathan Houze、Lixia Jin、Yihong Li、Yun Ling、Mei-Chu Lo、Alexander M. Long、Lawrence R. McGee、Joel McIntosh、Jonathan D. Oliner、Tao Osgood、Yosup Rew、Anne Y. Saiki、Paul Shaffer、Sarah Wortman、Peter Yakowec、Xuelei Yan、Qiuping Ye、Dongyin Yu、Xiaoning Zhao、Jing Zhou、Steven H. Olson、Daqing Sun、Julio C. Medina

  DOI：10.1021/jm401911v

  日期：2014.4.10

  We previously reported the discovery of potent and selective morpholinone and piperidinone inhibitors of the MDM2-p53 interaction. These inhibitors have in common a carboxylic acid moiety that engages in an electrostatic interaction with MDM2-His96. Our continued search for potent and diverse inhibitors led to the discovery of novel replacements for these acids uncovering new interactions with the MDM2 protein. In particular, using pyridine or thiazole as isosteres of the carboxylic acid moiety resulted in very potent analogues. From these, AM-6761 (4) emerged as a potent inhibitor with remarkable biochemical (HTRF IC50 = 0.1 nM) and cellular potency (SJSA-1 EdU IC50 = 16 nM), as well as favorable pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 11 mg/kg. Optimization efforts toward the discovery of these inhibitors as well as the new interactions observed with the MDM2 protein are described herein.