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)acetic acid | 1584731-94-1

• 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-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-chloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
• 英文别名: 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)acetic acid；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]acetic acid
• CAS: 1584731-94-1
• 化学式: C₂₉H₃₄Cl₂FNO₅S
• 分子量: 598.563
• InChiKey: IHUMWHKQAVMWCV-HXZUPTHJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  39
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  100
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  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)acetic acid 在 N-羟基-7-氮杂苯并三氮唑 、 水 、 碳酸氢钠 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 magnesium chloride 、 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 17.0h， 生成 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
  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
• 作为产物：
  描述：

  4-氯-3-氟苯甲酸 在 2,6-二甲基吡啶 、 sodium periodate 、 氯化亚砜 、 lithium hydroxide monohydrate 、 rhodium(III) chloride hydrate 、 4-甲苯磺酸酐 、 dichloro{(S)-(-)-2,2′-bis[di(3,5-xylyl)phosphino]-1,1′-binaphthyl}[(2S)-(+)-1,1-bis(4-methoxyphenyl)-3-methyl-1,2-butanediamine]ruthenium(II) 、 potassium tert-butylate 、 水 、 sodium hexamethyldisilazane 、 4-甲基苯磺酸吡啶 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 、 乙酸乙酯 、 甲苯 、 乙腈 为溶剂， -78.0~100.0 ℃ 、344.75 kPa 条件下， 反应 84.0h， 生成 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)acetic acid
  参考文献：
  名称：

  BENZOIC ACID DERIVATIVE MDM2 INHIBITOR FOR THE TREATMENT OF CANCER

  摘要：

  本发明提供了一种MDM2抑制剂化合物，或其药用可接受的盐，该化合物可作为治疗剂，特别是用于癌症治疗。本发明还涉及含有MDM2抑制剂的药物组合物。

  公开号：

  US20140243372A1

文献信息

• Benzoic acid derivative MDM2 inhibitor for the treatment of cancer
  申请人：Amgen Inc.

  公开号：US08952036B2

  公开（公告）日：2015-02-10

  The present invention provides a MDM2 inhibitor compound, or a pharmaceutically acceptable salt thereof, which compound is useful as a therapeutic agent, particularly for the treatment of cancers. The present invention also relates to pharmaceutical compositions that contains the MDM2 inhibitor.

  本发明提供了一种MDM2抑制剂化合物，或其药学上可接受的盐，该化合物可作为治疗剂，特别是用于治疗癌症。本发明还涉及包含MDM2抑制剂的制药组合物。
• Combination therapy including an MDM2 inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers
  申请人：AMGEN INC.

  公开号：US10881648B2

  公开（公告）日：2021-01-05

  The present invention provides combination therapy that includes an MDM2 inhibitor and one or more additional pharmaceutically active agents, particularly for the treatment of cancers. The invention also relates to pharmaceutical compositions that contain an MDM2 inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers.

  本发明提供了包括MDM2抑制剂和一种或多种额外的药学活性剂的组合疗法，特别是用于治疗癌症的组合疗法。 本发明还涉及用于治疗癌症的包含 MDM2 抑制剂和一种或多种额外药学活性剂的药物组合物。
• 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.
• [EN] COMBINATION THERAPY INCLUDING AN MDM2 INHIBITOR AND ONE OR MORE ADDITIONAL PHARMACEUTICALLY ACTIVE AGENTS FOR THE TREATMENT OF CANCERS<br/>[FR] POLYTHÉRAPIE COMPRENANT UN INHIBITEUR DE MDM2 ET UN OU PLUSIEURS PRINCIPES PHARMACEUTIQUEMENT ACTIFS SUPPLÉMENTAIRES POUR LE TRAITEMENT DE CANCERS
  申请人：AMGEN INC

  公开号：WO2015070224A3

  公开（公告）日：2015-08-13
• A BENZOIC ACID DERIVATIVE MDM2 INHIBITOR FOR THE TREATMENT OF CANCER
  申请人：Amgen Inc.

  公开号：EP2961735B1

  公开（公告）日：2017-09-27