(2S)-2-amino-N-[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]-3-phenylpropanamide | 1469983-03-6

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (2S)-2-amino-N-[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]-3-phenylpropanamide
• CAS: 1469983-03-6
• 化学式: C₁₈H₂₆N₂O₃
• 分子量: 318.416
• InChiKey: AHZURJPMSKEXJD-RLFYNMQTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  23
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  84.7
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (2S)-2-amino-N-[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]-3-phenylpropanamide 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 8.0h， 生成 N-{3-{(2S)-1-[(2S)-4-methyl-1-((2R)-2-methyloxiran-2-yl)-1-oxopentan-2-ylamino]-1-oxo-3-phenylpropan-2-ylamino}-3-oxo-1-phenylpropyl}benzamide
  参考文献：
  名称：

  Design, synthesis and biological evaluation of novel tripeptidyl epoxyketone derivatives constructed from β-amino acid as proteasome inhibitors

  摘要：

  A series of novel tripeptidyl epoxyketone derivatives constructed from beta-amino acid were designed, synthesized and evaluated as proteasome inhibitors. All target compounds were tested for their proteasome inhibitory activities and selected compounds were tested for their anti-proliferation activities against two multiple myeloma (MM) cell lines RPMI 8226 and NCI-H929. Among them, eleven compounds exhibited proteasome inhibitory rates of more than 50% at the concentration of 1 mu g/mL and nine compounds showed anti-proliferation activities with IC50 values at low micromolar level. Compound 20h displayed the most potent proteasome inhibitory activities (IC50: 0.11 +/- 0.01 mu M) and anti-proliferation activities with IC50 values at 0.23 +/- 0.01 and 0.17 +/- 0.02 mu M against two tested cell lines. Additionally, the poly-ubiquitin accumulation in the western blot analysis supported that proteasome inhibition in a cellular system was induced by compound 20h. All these experimental results confirmed that b-amino acid can be introduced as a building block for the development of proteasome inhibitors. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2014.04.011
• 作为产物：
  描述：

  (2S)-2-氨基-4-甲基-1-[(2R)-2-甲基环氧乙烷基]-1-戊酮 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 4.5h， 生成 (2S)-2-amino-N-[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]-3-phenylpropanamide
  参考文献：
  名称：

  Design, synthesis and biological evaluation of novel tripeptidyl epoxyketone derivatives constructed from β-amino acid as proteasome inhibitors

  摘要：

  A series of novel tripeptidyl epoxyketone derivatives constructed from beta-amino acid were designed, synthesized and evaluated as proteasome inhibitors. All target compounds were tested for their proteasome inhibitory activities and selected compounds were tested for their anti-proliferation activities against two multiple myeloma (MM) cell lines RPMI 8226 and NCI-H929. Among them, eleven compounds exhibited proteasome inhibitory rates of more than 50% at the concentration of 1 mu g/mL and nine compounds showed anti-proliferation activities with IC50 values at low micromolar level. Compound 20h displayed the most potent proteasome inhibitory activities (IC50: 0.11 +/- 0.01 mu M) and anti-proliferation activities with IC50 values at 0.23 +/- 0.01 and 0.17 +/- 0.02 mu M against two tested cell lines. Additionally, the poly-ubiquitin accumulation in the western blot analysis supported that proteasome inhibition in a cellular system was induced by compound 20h. All these experimental results confirmed that b-amino acid can be introduced as a building block for the development of proteasome inhibitors. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2014.04.011

文献信息

• [EN] PEGYLATED CARFILZOMIB COMPOUNDS<br/>[FR] COMPOSÉS DE CARFILZOMIB PÉGYLÉS
  申请人：AMGEN INC

  公开号：WO2017205392A1

  公开（公告）日：2017-11-30

  The present invention provides polymeric pegylated carfilzomib compounds, and pharmaceutically acceptable salts thereof, of Formula I wherein R1, R2, linker, PEG, n and o are as defined herein. The invention also provides methods of making and using these compounds to treat cancer, and particularly to treat hematological malignancies including multiple myeloma.

  本发明提供了聚合物PEG化的卡菲索米布化合物及其药用盐，其化学式为I，其中R1、R2、连接基、PEG、n和o如本文所定义。本发明还提供了制备和使用这些化合物来治疗癌症，特别是治疗包括多发性骨髓瘤在内的血液恶性肿瘤的方法。
• PROCESSES FOR THE PREPARATION OF CARFILZOMIB OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
  申请人：LAURUS LABS LIMITED

  公开号：US20190284231A1

  公开（公告）日：2019-09-19

  The present invention relates to an improved process for the preparation of carfilzomib or a pharmaceutically acceptable salt thereof. The present invention also relates to a process for the preparation of amorphous form of carfilzomib.

  本发明涉及一种改进的制备卡非索米或其药学上可接受的盐的方法。本发明还涉及一种制备卡非索米非晶态的方法。
• Processes for the preparation of carfilzomib or pharmaceutically acceptable salts thereof
  申请人：LAURUS LABS PRIVATE LIMITED

  公开号：US10364269B2

  公开（公告）日：2019-07-30

  The present invention relates to an improved process for the preparation of carfilzomib or a pharmaceutically acceptable salt thereof. The present invention also relates to a process for the preparation of amorphous form of carfilzomib.

  本发明涉及一种制备卡非佐米或其药学上可接受的盐的改进工艺。本发明还涉及一种制备无定形卡非佐米的工艺。
• AN IMPROVED PROCESSES FOR THE PREPARATION OF CARFILZOMIB OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
  申请人：LAURUS LABS PRIVATE LIMITED

  公开号：US20190085026A1

  公开（公告）日：2019-03-21

  The present invention relates to an improved process for the preparation of carfilzomib or a pharmaceutically acceptable salt thereof. The present invention also relates to a process for the preparation of amorphous form of carfilzomib.
• Covalent docking modelling-based discovery of tripeptidyl epoxyketone proteasome inhibitors composed of aliphatic-heterocycles
  作者：Xiao-Wu Dong、Jian-Kang Zhang、Lei Xu、Jin-Xin Che、Gang Cheng、Xiao-Bei Hu、Li Sheng、An-Hui Gao、Jia Li、Tao Liu、Yong-Zhou Hu、Yu-Bo Zhou

  DOI：10.1016/j.ejmech.2018.12.064

  日期：2019.2

  The potential of specific proteasome inhibitors to act as anti-cancer agents has attracted intensive investigations. The proteasome can be covalently inhibited by epoxyketone derivatives via a two-step reaction. Several computational approaches have been developed to mimic the covalent binding event. Compound 1 composed of a six-membered heterocyclic ring was designed by using covalent docking. With a possible different binding mode from the clinical compound Carfilzomib, it occupied the 55 pocket of 20S proteasome and showed favorable inhibitory activity. Subsequently optimization and evaluation were taken place. Among these compounds, 11h demonstrated extraordinary in vitro inhibitory activity and selectivity, and good in vivo proteasome inhibitory activity, a favorable pharmacokinetic profile and xenograft tumor inhibition. The possible binding pattern of compound 11h against proteasome was further fully explored via calculations, providing a theoretical basis for finding potent proteasome inhibitors. (C) 2018 Elsevier Masson SAS. All rights reserved.