3-[5-[[(2S)-3-[4-(2-carboxy-N-oxaloanilino)naphthalen-1-yl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]amino]pentoxy]naphthalene-2-carboxylic acid | 521274-10-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: 3-[5-[[(2S)-3-[4-(2-carboxy-N-oxaloanilino)naphthalen-1-yl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]amino]pentoxy]naphthalene-2-carboxylic acid
• CAS: 521274-10-2
• 化学式: C₄₃H₄₃N₃O₁₁
• 分子量: 777.828
• InChiKey: UEOZPFQJMWBDGL-XIFFEERXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.4
• 重原子数：
  57
• 可旋转键数：
  18
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  209
• 氢给体数：
  5
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  3-[5-[[(2S)-3-[4-(2-carboxy-N-oxaloanilino)naphthalen-1-yl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]amino]pentoxy]naphthalene-2-carboxylic acid 在 sodium hydroxide 、 三氟乙酸 作用下， 反应 0.67h， 生成 (S)-3-({5-[(N-acetyl-3-{4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-1-naphthyl}-L-alanyl)amino]pentyl}oxy)-2-naphthoic acid
  参考文献：
  名称：

  Discovery of a Potent, Selective Protein Tyrosine Phosphatase 1B Inhibitor Using a Linked-Fragment Strategy

  摘要：

  Protein tyrosine phosphatase 1B (PTP1B) is an enzyme that downregulates the insulin receptor. Inhibition of PTP1B is expected to improve insulin action, and the design of small molecule PTP1B inhibitors to treat type II diabetes has received considerable attention. In this work, NMR-based screening identified a nonselective competitive inhibitor of PTP1B. A second site ligand was also identified by NMR-based screening and then linked to the catalytic site ligand by rational design. X-ray data confirmed that the inhibitor bound with the catalytic site in the native, "open" conformation. The final compound displayed excellent potency and good selectivity over many other phosphatases. The modular approach to drug design described in this work should be applicable for the design of potent and selective inhibitors of other therapeutically relevant protein tyrosine phosphatases.

  DOI：

  10.1021/ja0296733
• 作为产物：
  描述：

  5-(N-叔丁氧羰基氨基)-1-戊醇 在 N-甲基吗啉 、 盐酸 、 sodium hydroxide 、 copper diacetate 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 异丙醇 为溶剂， 反应 54.92h， 生成 3-[5-[[(2S)-3-[4-(2-carboxy-N-oxaloanilino)naphthalen-1-yl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]amino]pentoxy]naphthalene-2-carboxylic acid
  参考文献：
  名称：

  Discovery of a Potent, Selective Protein Tyrosine Phosphatase 1B Inhibitor Using a Linked-Fragment Strategy

  摘要：

  Protein tyrosine phosphatase 1B (PTP1B) is an enzyme that downregulates the insulin receptor. Inhibition of PTP1B is expected to improve insulin action, and the design of small molecule PTP1B inhibitors to treat type II diabetes has received considerable attention. In this work, NMR-based screening identified a nonselective competitive inhibitor of PTP1B. A second site ligand was also identified by NMR-based screening and then linked to the catalytic site ligand by rational design. X-ray data confirmed that the inhibitor bound with the catalytic site in the native, "open" conformation. The final compound displayed excellent potency and good selectivity over many other phosphatases. The modular approach to drug design described in this work should be applicable for the design of potent and selective inhibitors of other therapeutically relevant protein tyrosine phosphatases.

  DOI：

  10.1021/ja0296733

文献信息

• Discovery of a Potent, Selective Protein Tyrosine Phosphatase 1B Inhibitor Using a Linked-Fragment Strategy
  作者：Bruce G. Szczepankiewicz、Gang Liu、Philip J. Hajduk、Cele Abad-Zapatero、Zhonghua Pei、Zhili Xin、Thomas H. Lubben、James M. Trevillyan、Michael A. Stashko、Stephen J. Ballaron、Heng Liang、Flora Huang、Charles W. Hutchins、Stephen W. Fesik、Michael R. Jirousek

  DOI：10.1021/ja0296733

  日期：2003.4.1

  Protein tyrosine phosphatase 1B (PTP1B) is an enzyme that downregulates the insulin receptor. Inhibition of PTP1B is expected to improve insulin action, and the design of small molecule PTP1B inhibitors to treat type II diabetes has received considerable attention. In this work, NMR-based screening identified a nonselective competitive inhibitor of PTP1B. A second site ligand was also identified by NMR-based screening and then linked to the catalytic site ligand by rational design. X-ray data confirmed that the inhibitor bound with the catalytic site in the native, "open" conformation. The final compound displayed excellent potency and good selectivity over many other phosphatases. The modular approach to drug design described in this work should be applicable for the design of potent and selective inhibitors of other therapeutically relevant protein tyrosine phosphatases.