2-[(2R,5S,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopropylmethyl)-3-oxomorpholin-2-yl]acetic 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: 2-[(2R,5S,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopropylmethyl)-3-oxomorpholin-2-yl]acetic acid
• 化学式: C₂₂H₂₁Cl₂NO₄
• 分子量: 434.319
• InChiKey: PLSLYOZGYCPTIL-GIVPXCGWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  29
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  66.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  DL-对氯苯甘氨酸 在 sodium tetrahydroborate 、 sodium periodate 、 ruthenium(III) trichloride hydrate 、 sodium hexamethyldisilazane 、 sodium hydride 、 1-羟基苯并三唑 、 caesium carbonate 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 三乙胺 、 N,N-二异丙基乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 四氯化碳 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 丙酮 、 乙腈 、 mineral oil 为溶剂， 反应 95.07h， 生成 2-[(2R,5S,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopropylmethyl)-3-oxomorpholin-2-yl]acetic acid
  参考文献：
  名称：

  Rational Design and Binding Mode Duality of MDM2–p53 Inhibitors

  摘要：

  Structural analysis of both the MDM2-p53 protein protein interaction and several small molecules bound to MDM2 led to the design and synthesis of tetrasubstituted morpholinone 10, an MDM2 inhibitor with a biochemical IC50 of 1.0 mu M. The cocrystal structure of 10 with MDM2 inspired two independent optimization strategies and resulted in the discovery of morpholinones 16 and 27 possessing distinct binding modes. Both analogues were potent MDM2 inhibitors in biochemical and cellular assays, and morpholinone 27 (IC50 = 0.10 mu M) also displayed suitable PK profile for in vivo animal experiments. A pharmacodynamic (PD) experiment in mice implanted with human SJSA-1 tumors showed p21(WAFl) mRNA induction (2.7-fold over vehicle) upon oral dosing of 27 at 300 mg/kg.

  DOI：

  10.1021/jm400293z

文献信息

• [EN] HETEROCYCLIC COMPOUNDS AS MDM2 INHIBITORS FOR THE TREATMENT OF CANCER<br/>[FR] HETEROCYCLES UTILISES COMME INHIBITEURS DE MDM2 DANS LE TRAITEMENT DU CANCER
  申请人：AMGEN INC

  公开号：WO2013049250A1

  公开（公告）日：2013-04-04

  The present invention provides MDM2 inhibitor compounds of Formula I or II, or the pharmaceutically acceptable salts thereof, wherein the variables are defined above, which compounds are useful as therapeutic agents, particularly for the treatment of cancers. The present invention also relates to pharmaceutical compositions that contain an MDM2 inhibitor.

  本发明提供了化合物I或II的MDM2抑制剂，或其药用盐，其中上述变量已定义，这些化合物可用作治疗剂，特别用于癌症的治疗。本发明还涉及含有MDM2抑制剂的药物组合物。
• HETEROCYCLIC COMPOUNDS AS MDM2 INHIBITORS FOR THE TREATMENT OF CANCER
  申请人：AMGEN INC.

  公开号：US20140235629A1

  公开（公告）日：2014-08-21

  The present invention provides MDM2 inhibitor compounds of Formula I or II, or the pharmaceutically acceptable salts thereof, wherein the variables are defined above, which compounds are useful as therapeutic agents, particularly for the treatment of cancers. The present invention also relates to pharmaceutical compositions that contain an MDM2 inhibitor.

  本发明提供了公式I或II的MDM2抑制剂化合物，或其药学上可接受的盐，其中变量如上所定义，这些化合物可用作治疗剂，尤其是用于癌症的治疗。本发明还涉及含有MDM2抑制剂的药物组合物。
• US9376425B2
  申请人：——

  公开号：US9376425B2

  公开（公告）日：2016-06-28
• Rational Design and Binding Mode Duality of MDM2–p53 Inhibitors
  作者：Felix Gonzalez-Lopez de Turiso、Daqing Sun、Yosup Rew、Michael D. Bartberger、Hilary P. Beck、Jude Canon、Ada Chen、David Chow、Tiffany L. Correll、Xin Huang、Lisa D. Julian、Frank Kayser、Mei-Chu Lo、Alexander M. Long、Dustin McMinn、Jonathan D. Oliner、Tao Osgood、Jay P. Powers、Anne Y. Saiki、Steve Schneider、Paul Shaffer、Shou-Hua Xiao、Peter Yakowec、Xuelei Yan、Qiuping Ye、Dongyin Yu、Xiaoning Zhao、Jing Zhou、Julio C. Medina、Steven H. Olson

  DOI：10.1021/jm400293z

  日期：2013.5.23

  Structural analysis of both the MDM2-p53 protein protein interaction and several small molecules bound to MDM2 led to the design and synthesis of tetrasubstituted morpholinone 10, an MDM2 inhibitor with a biochemical IC50 of 1.0 mu M. The cocrystal structure of 10 with MDM2 inspired two independent optimization strategies and resulted in the discovery of morpholinones 16 and 27 possessing distinct binding modes. Both analogues were potent MDM2 inhibitors in biochemical and cellular assays, and morpholinone 27 (IC50 = 0.10 mu M) also displayed suitable PK profile for in vivo animal experiments. A pharmacodynamic (PD) experiment in mice implanted with human SJSA-1 tumors showed p21(WAFl) mRNA induction (2.7-fold over vehicle) upon oral dosing of 27 at 300 mg/kg.