4-(4-acryloylaminobenzenesulfonyl)piperazine-1-carboxylic acid 2-methylbenzyl ester | 1306720-31-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 4-(4-acryloylaminobenzenesulfonyl)piperazine-1-carboxylic acid 2-methylbenzyl ester
• 英文别名: (2-Methylphenyl)methyl 4-[4-(prop-2-enoylamino)phenyl]sulfonylpiperazine-1-carboxylate
• CAS: 1306720-31-9
• 化学式: C₂₂H₂₅N₃O₅S
• 分子量: 443.524
• InChiKey: FDPHLPHLATXLCE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  31
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  104
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  N-((4-硝基苯基)磺酰基)-1-(叔丁基氧基羰基)哌嗪 在 铁粉 、 氯化铵 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 22.0h， 生成 4-(4-acryloylaminobenzenesulfonyl)piperazine-1-carboxylic acid 2-methylbenzyl ester
  参考文献：
  名称：

  Discovery and Structure–Activity Relationship of Potent and Selective Covalent Inhibitors of Transglutaminase 2 for Huntington’s Disease

  摘要：

  Tissue transglutaminase 2 (TG2) is a multifunctional protein primarily known for its calcium-dependent enzymatic protein cross-linking activity via isopeptide bond formation between glutamine and lysine residues. TG2 overexpression and activity have been found to be associated with Huntington's disease (HD); specifically, TG2 is up-regulated in the brains of HD patients and in animal models of the disease. Interestingly, genetic deletion of TG2 in two different HD mouse models, R6/1 and R6/2, results in improved phenotypes including a reduction in neuronal death and prolonged survival. Starting with phenylacrylamide screening hit 7d, we describe the SAR of this series leading to potent and selective TG2 inhibitors. The suitability of the compounds as in vitro tools to elucidate the biology of TG2 was demonstrated through mode of inhibition studies, characterization of druglike properties, and inhibition profiles in a cell lysate assay.

  DOI：

  10.1021/jm201310y

文献信息

• [EN] TRANSGLUTAMINASE TG2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND METHODS OF USE THEREOF<br/>[FR] INHIBITEURS DE TRANSGLUTAMINASE TG2, COMPOSITIONS PHARMACEUTIQUES ET LEURS PROCÉDÉS D'UTILISATION
  申请人：CHDI INC

  公开号：WO2011060321A1

  公开（公告）日：2011-05-19

  Certain compounds and pharmaceutically acceptable salts are provided herein. Also provided are pharmaceutical compositions comprising at least one compound or pharmaceutically acceptable salt therein and one or more pharmaceutically acceptable vehicle. Methods of treating patients suffering from certain disease states responsive to the inhibition of transglutaminase TG2 activity are described. These disease states include neurodegenerative disorders such as Huntington's disease. Also described are methods of treatment include administering at least one compound or pharmaceutically acceptable salt thereof as a single active agent or administering at least one compound or pharmaceutically acceptable salt thereof in combination with one or more other therapeutic agents.

  本文提供了某些化合物和药学上可接受的盐。还提供了包括至少一种化合物或其中的药学上可接受的盐以及一种或多种药学上可接受的载体的药物组合物。描述了治疗对转谷氨酰胺酶TG2活性抑制产生响应的患有某些疾病状态的患者的方法。这些疾病状态包括神经退行性疾病，如亨廷顿病。还描述了治疗方法，包括单独给予至少一种化合物或其中的药学上可接受的盐，或者将至少一种化合物或其中的药学上可接受的盐与一种或多种其他治疗剂结合给予。
• TRANSGLUTAMINASE TG2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND METHODS OF USE THEREOF
  申请人：Dominguez Celia

  公开号：US20130116216A1

  公开（公告）日：2013-05-09

  Certain compounds and pharmaceutically acceptable salts are provided herein. Also provided are pharmaceutical compositions comprising at least one compound or pharmaceutically acceptable salt therein and one or more pharmaceutically acceptable vehicle. Methods of treating patients suffering from certain disease states responsive to the inhibition of transglutaminase TG2 activity are described. These disease states include neurodegenerative disorders such as Huntington's disease. Also described are methods of treatment include administering at least one compound or pharmaceutically acceptable salt thereof as a single active agent or administering at least one compound or pharmaceutically acceptable salt thereof in combination with one or more other therapeutic agents.

  本文提供了某些化合物和药用可接受的盐。还提供了包含至少一种该化合物或药用可接受的盐和一种或多种药用可接受载体的制药组合物。描述了治疗对抑制转麦芽氨酰胺酶TG2活性响应的某些疾病状态的患者的方法。这些疾病状态包括神经退行性疾病，如亨廷顿病。还描述了治疗方法，包括单独使用至少一种该化合物或药用可接受的盐作为活性剂，或与一种或多种其他治疗剂联合使用至少一种该化合物或药用可接受的盐。
• US8946197B2
  申请人：——

  公开号：US8946197B2

  公开（公告）日：2015-02-03
• Discovery and Structure–Activity Relationship of Potent and Selective Covalent Inhibitors of Transglutaminase 2 for Huntington’s Disease
  作者：Michael E. Prime、Ole A. Andersen、John J. Barker、Mark A. Brooks、Robert K. Y. Cheng、Ian Toogood-Johnson、Stephen M. Courtney、Frederick A. Brookfield、Christopher J. Yarnold、Richard W. Marston、Peter D. Johnson、Siw F. Johnsen、Jordan J. Palfrey、Darshan Vaidya、Sayeh Erfan、Osamu Ichihara、Brunella Felicetti、Shilpa Palan、Anna Pedret-Dunn、Sabine Schaertl、Ina Sternberger、Andreas Ebneth、Andreas Scheel、Dirk Winkler、Leticia Toledo-Sherman、Maria Beconi、Douglas Macdonald、Ignacio Muñoz-Sanjuan、Celia Dominguez、John Wityak

  DOI：10.1021/jm201310y

  日期：2012.2.9

  Tissue transglutaminase 2 (TG2) is a multifunctional protein primarily known for its calcium-dependent enzymatic protein cross-linking activity via isopeptide bond formation between glutamine and lysine residues. TG2 overexpression and activity have been found to be associated with Huntington's disease (HD); specifically, TG2 is up-regulated in the brains of HD patients and in animal models of the disease. Interestingly, genetic deletion of TG2 in two different HD mouse models, R6/1 and R6/2, results in improved phenotypes including a reduction in neuronal death and prolonged survival. Starting with phenylacrylamide screening hit 7d, we describe the SAR of this series leading to potent and selective TG2 inhibitors. The suitability of the compounds as in vitro tools to elucidate the biology of TG2 was demonstrated through mode of inhibition studies, characterization of druglike properties, and inhibition profiles in a cell lysate assay.