N1-(2-carboxyl)benzoyl-N5-(2-chloro-1-iminoethyl)-1-(1-methylbenzo[d]imidazol-2-yl)-L-ornithine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: N1-(2-carboxyl)benzoyl-N5-(2-chloro-1-iminoethyl)-1-(1-methylbenzo[d]imidazol-2-yl)-L-ornithine
• 英文别名: 2-[[(1S)-4-[(1-amino-2-chloroethylidene)amino]-1-(1-methylbenzimidazol-2-yl)butyl]carbamoyl]benzoic acid
• 化学式: C₂₂H₂₄ClN₅O₃
• 分子量: 441.917
• InChiKey: YRMGAQBSNCRDKM-KRWDZBQOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  31
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  123
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  N-甲基-1,2-苯二胺 在 哌啶 、 1-羟基苯并三唑 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 三乙胺 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 49.33h， 生成 N1-(2-carboxyl)benzoyl-N5-(2-chloro-1-iminoethyl)-1-(1-methylbenzo[d]imidazol-2-yl)-L-ornithine
  参考文献：
  名称：

  Development of a Selective Inhibitor of Protein Arginine Deiminase 2

  摘要：

  Protein arginine deiminase 2 (PAD2) plays a key role in the onset and progression of multiple sclerosis, rheumatoid arthritis, and breast cancer. To date, no PAD2-selective inhibitor has been developed. Such a compound will be critical for elucidating the biological roles of this isozyme and may ultimately be useful for treating specific diseases in which PAD2 activity is dysregulated. To achieve this goal, we synthesized a series of benzimidazole-based derivatives of Cl-amidine, hypothesizing that this scaffold would allow access to a series of PAD2-selective inhibitors with enhanced cellular efficacy. Herein, we demonstrate that substitutions at both the N-terminus and C-terminus of Cl-amidine result in >100-fold increases in PAD2 potency and selectivity (30a, 41a, and 49a) as well as cellular efficacy (30a). Notably, these compounds use the far less reactive fluoroacetamidine warhead. In total, we predict that 30a will be a critical tool for understanding cellular PAD2 function and sets the stage for treating diseases in which PAD2 activity is dysregulated.

  DOI：

  10.1021/acs.jmedchem.7b00274

文献信息

• [EN] INHIBITORS OF PROTEIN ARGININE DEIMINASES (PADS) AND METHODS OF PREPARATION AND USE THEREOF<br/>[FR] INHIBITEURS DE PROTÉINE ARGININE DÉIMINASES (PAD) ET PROCÉDÉS DE PRÉPARATION ET D'UTILISATION ASSOCIÉS
  申请人：UNIV MASSACHUSETTS

  公开号：WO2018102262A1

  公开（公告）日：2018-06-07

  The invention provides novel inhibitors or inactivators of protein arginine deiminases, pharmaceutical compositions and methods of use thereof. The invention also relates to molecular probes based on such compounds and methods of use thereof.

  这项发明提供了新型的蛋白精氨酸去亚氨基酶抑制剂或失活剂，以及其药物组合物和使用方法。该发明还涉及基于这些化合物的分子探针以及其使用方法。
• Inhibitors of protein arginine deiminases (PADs) and methods of preparation and use thereof
  申请人：University of Massachusetts

  公开号：US11208386B2

  公开（公告）日：2021-12-28

  The invention provides novel inhibitors or inactivators of protein arginine deiminases, pharmaceutical compositions and methods of use thereof. The invention also relates to molecular probes based on such compounds and methods of use thereof.

  本发明提供了蛋白质精氨酸脱亚胺酶的新型抑制剂或灭活剂、药物组合物及其使用方法。本发明还涉及基于此类化合物的分子探针及其使用方法。
• INHIBITORS OF PROTEIN ARGININE DEIMINASES (PADS) AND METHODS OF PREPARATION AND USE THEREOF
  申请人：University of Massachusetts

  公开号：US20200339518A1

  公开（公告）日：2020-10-29

  The invention provides novel inhibitors or inactivators of protein arginine deiminases, pharmaceutical compositions and methods of use thereof. The invention also relates to molecular probes based on such compounds and methods of use thereof.
• Development of a Selective Inhibitor of Protein Arginine Deiminase 2
  作者：Aaron Muth、Venkataraman Subramanian、Edward Beaumont、Mitesh Nagar、Philip Kerry、Paul McEwan、Hema Srinath、Kathleen Clancy、Sangram Parelkar、Paul R. Thompson

  DOI：10.1021/acs.jmedchem.7b00274

  日期：2017.4.13

  Protein arginine deiminase 2 (PAD2) plays a key role in the onset and progression of multiple sclerosis, rheumatoid arthritis, and breast cancer. To date, no PAD2-selective inhibitor has been developed. Such a compound will be critical for elucidating the biological roles of this isozyme and may ultimately be useful for treating specific diseases in which PAD2 activity is dysregulated. To achieve this goal, we synthesized a series of benzimidazole-based derivatives of Cl-amidine, hypothesizing that this scaffold would allow access to a series of PAD2-selective inhibitors with enhanced cellular efficacy. Herein, we demonstrate that substitutions at both the N-terminus and C-terminus of Cl-amidine result in >100-fold increases in PAD2 potency and selectivity (30a, 41a, and 49a) as well as cellular efficacy (30a). Notably, these compounds use the far less reactive fluoroacetamidine warhead. In total, we predict that 30a will be a critical tool for understanding cellular PAD2 function and sets the stage for treating diseases in which PAD2 activity is dysregulated.