1-(2-吡嗪基羰基)-4-哌啶甲酸 | 926211-24-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 中文名称: 1-(2-吡嗪基羰基)-4-哌啶甲酸
• 英文名称: 1-(pyrazine-2-carbonyl)-piperidine-4-carboxylic acid
• 英文别名: 1-(pyrazin-2-oyl)piperidine-4-carboxylic acid；1-(Pyrazine-2-carbonyl)piperidine-4-carboxylic acid
• CAS: 926211-24-7
• 化学式: C₁₁H₁₃N₃O₃
• mdl: MFCD09042750
• 分子量: 235.243
• InChiKey: NQOKNPZWACZTRC-UHFFFAOYSA-N

物化性质

• 密度：
  1.357

计算性质

• 辛醇/水分配系数(LogP)：
  -0.4
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.454
• 拓扑面积：
  83.4
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-(2-吡嗪基羰基)-4-哌啶甲酸 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 、 lithium hydroxide 作用下， 以 二氯甲烷 、 水 、 丙酮 为溶剂， 反应 7.5h， 生成 N-((S)-4-methyl-1-(((S)-1-(((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopentan-2-yl)-1-(pyrazine-2-carbonyl)piperidine-4-carboxamide
  参考文献：
  名称：

  Covalent docking modelling-based discovery of tripeptidyl epoxyketone proteasome inhibitors composed of aliphatic-heterocycles

  摘要：

  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.

  DOI：

  10.1016/j.ejmech.2018.12.064
• 作为产物：
  描述：

  4-哌啶甲酸甲酯 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 、 lithium hydroxide 作用下， 以 二氯甲烷 、 水 、 丙酮 为溶剂， 反应 4.5h， 生成 1-(2-吡嗪基羰基)-4-哌啶甲酸
  参考文献：
  名称：

  探索新的哌嗪或哌啶构建的非共价肽基衍生物作为蛋白酶体抑制剂

  摘要：

  设计，合成和评价了一系列具有新戊基-天冬酰胺残基的新的哌嗪或含哌啶的非共价肽基衍生物，并评价它们为蛋白酶体抑制剂。筛选了所有目标化合物的20S蛋白酶体胰凝乳蛋白酶样抑制活性，其中15种化合物比卡非佐米具有更强的活性，IC 50值低于10 nM。随后，测试了最有效的10种类似物对两种多发性骨髓瘤（MM）细胞系RPMI-8226和MM-1S的细胞毒活性。基于这些实验，进一步评估了所选衍生物的离体和体内血细胞蛋白酶体抑制活性。最有潜力的化合物35（蛋白酶体抑制IC 50：1.2±0.1 nM），具有有效的抗增殖作用（IC 50：RPMI-8226 8.4±0.8 nM； MM-1S：6.3±0.8 nM），离体和体内活性也具有延长的半衰期在血浆中的抗性，这表明通过在肽骨架中构建六元环可提高该系列化合物的酶稳定性。所有的实验都证实了设计概念的正确性，这使得该系列化合物成为探索新的抗MM药物的潜在线索。

  DOI：

  10.1016/j.ejmech.2016.12.034

文献信息

• Exploration of novel piperazine or piperidine constructed non-covalent peptidyl derivatives as proteasome inhibitors
  作者：Rangxiao Zhuang、Lixin Gao、Xiaoqing Lv、Jianjun Xi、Li Sheng、Yanmei Zhao、Ruoyu He、Xiaobei Hu、Yidan Shao、Xuwang Pan、Shourong Liu、Weiwei Huang、Yubo Zhou、Jia Li、Jiankang Zhang

  DOI：10.1016/j.ejmech.2016.12.034

  日期：2017.1

  A series of novel piperazine or piperidine-containing non-covalent peptidyl derivatives possessing a neopentyl-asparagine residue were designed, synthesized and evaluated as proteasome inhibitors. All target compounds were screened for their 20S proteasome chymotrypsin-like inhibitory activities, and 15 ones displayed more potent activities than carfilzomib with IC50 values lower than 10 nM. Subsequently

  设计，合成和评价了一系列具有新戊基-天冬酰胺残基的新的哌嗪或含哌啶的非共价肽基衍生物，并评价它们为蛋白酶体抑制剂。筛选了所有目标化合物的20S蛋白酶体胰凝乳蛋白酶样抑制活性，其中15种化合物比卡非佐米具有更强的活性，IC 50值低于10 nM。随后，测试了最有效的10种类似物对两种多发性骨髓瘤（MM）细胞系RPMI-8226和MM-1S的细胞毒活性。基于这些实验，进一步评估了所选衍生物的离体和体内血细胞蛋白酶体抑制活性。最有潜力的化合物35（蛋白酶体抑制IC 50：1.2±0.1 nM），具有有效的抗增殖作用（IC 50：RPMI-8226 8.4±0.8 nM； MM-1S：6.3±0.8 nM），离体和体内活性也具有延长的半衰期在血浆中的抗性，这表明通过在肽骨架中构建六元环可提高该系列化合物的酶稳定性。所有的实验都证实了设计概念的正确性，这使得该系列化合物成为探索新的抗MM药物的潜在线索。
• 2-Amido-4-phenylthiazole Derivatives, The Preparation And The Therapeutic Use Thereof
  申请人：CASELLAS Pierre

  公开号：US20070259847A1

  公开（公告）日：2007-11-08

  The disclosure relates to 2-amido-4-phenylthiazole derivatives of general formula (I) below: in which R 1 , R 2 , R 3 , Y, m, n, and p are as defined in the disclosure; as well as to their isomers, salts and solvates, to the pharmaceutical compositions containing them and to the therapeutic use thereof.

  该公开涉及通式（I）如下的2-酰胺-4-苯基噻唑衍生物：其中R1、R2、R3、Y、m、n和p如公开所定义；以及它们的异构体、盐和溶剂合物，包含它们的药物组合物以及其治疗用途。
• US7598392B2
  申请人：——

  公开号：US7598392B2

  公开（公告）日：2009-10-06
• 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.