2-[[(2R)-5-[(1-amino-2-chloroethylidene)amino]-2-benzamidopentanoyl]amino]acetic acid | 1404060-21-4

• 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: 2-[[(2R)-5-[(1-amino-2-chloroethylidene)amino]-2-benzamidopentanoyl]amino]acetic acid
• CAS: 1404060-21-4
• 化学式: C₁₆H₂₁ClN₄O₄
• 分子量: 368.82
• InChiKey: QZQICDRPHXCFNP-GFCCVEGCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  25
• 可旋转键数：
  10
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  134
• 氢给体数：
  4
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  Fmoc-gly-wang resin 、 Fmoc-D-Orn(DDE)-OH 、 2-氯-1-乙氧基乙胺 、 苯甲酸 在 哌啶 、 N-甲基吗啉 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.17h， 以45.8%的产率得到2-[[(2R)-5-[(1-amino-2-chloroethylidene)amino]-2-benzamidopentanoyl]amino]acetic acid
  参考文献：
  名称：

  d-Amino Acid-Based Protein Arginine Deiminase Inhibitors: Synthesis, Pharmacokinetics, and in Cellulo Efficacy

  摘要：

  The protein arginine deiminases (PADs) are known to play a crucial role in the onset and progression of multiple inflammatory diseases, including rheumatoid arthritis, inflammatory bowel disease, and cancer. However, it is not known how each of the five PAD isozymes contributes to disease pathogenesis. As such, potent, selective, and bioavailable PAD inhibitors will be useful chemical probes to elucidate the specific roles of each isozyme. Because D-amino amino acids often possess enhanced in cellulo stability, and perhaps unique selectivities, we synthesized a series of D-amino acid analogues of our Pan-PAD inhibitor Cl-amicline, hypothesizing that this change would provide inhibitors with enhanced pharmacokinetic properties. Herein, we demonstrate that D-Cl-amidine and D-o-F-amidine are potent and highly selective inhibitors of PAD1. The pharmacokinetic properties of D-Cl-amidine were moderately improved over those of L-Cl-amidine, and this compound exhibited similar cell killing in a PAD1 expressing, triple-negative MDA-MB-231 breast cancer cell line. These inhibitors represent an important step in our efforts to develop stable, bioavailable, and highly selective inhibitors for all of the PAD isozymes.

  DOI：

  10.1021/ml300288d

文献信息

• <scp>d</scp>-Amino Acid-Based Protein Arginine Deiminase Inhibitors: Synthesis, Pharmacokinetics, and in Cellulo Efficacy
  作者：Kevin L. Bicker、Lynne Anguish、Alexander A. Chumanevich、Michael D. Cameron、Xiangli Cui、Erin Witalison、Venkataraman Subramanian、Xuesen Zhang、Alena P. Chumanevich、Lorne J. Hofseth、Scott A. Coonrod、Paul R. Thompson

  DOI：10.1021/ml300288d

  日期：2012.12.13

  The protein arginine deiminases (PADs) are known to play a crucial role in the onset and progression of multiple inflammatory diseases, including rheumatoid arthritis, inflammatory bowel disease, and cancer. However, it is not known how each of the five PAD isozymes contributes to disease pathogenesis. As such, potent, selective, and bioavailable PAD inhibitors will be useful chemical probes to elucidate the specific roles of each isozyme. Because D-amino amino acids often possess enhanced in cellulo stability, and perhaps unique selectivities, we synthesized a series of D-amino acid analogues of our Pan-PAD inhibitor Cl-amicline, hypothesizing that this change would provide inhibitors with enhanced pharmacokinetic properties. Herein, we demonstrate that D-Cl-amidine and D-o-F-amidine are potent and highly selective inhibitors of PAD1. The pharmacokinetic properties of D-Cl-amidine were moderately improved over those of L-Cl-amidine, and this compound exhibited similar cell killing in a PAD1 expressing, triple-negative MDA-MB-231 breast cancer cell line. These inhibitors represent an important step in our efforts to develop stable, bioavailable, and highly selective inhibitors for all of the PAD isozymes.