2-[[(4-{2-[(1-benzofuran-2-ylcarbonyl)amino]ethoxy}phenyl)sulfonyl](benzyl)amino]-3,5-dimethylbenzoic acid | 306956-35-4

• 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: 2-[[(4-{2-[(1-benzofuran-2-ylcarbonyl)amino]ethoxy}phenyl)sulfonyl](benzyl)amino]-3,5-dimethylbenzoic acid
• 英文别名: [(4-{2-[(Benzofuran-2-carbonyl)-amino]ethoxy}benzenesulfonyl]benzylamino]-3,5-dimethyl-benzoic Acid；2-[[4-[2-(1-benzofuran-2-carbonylamino)ethoxy]phenyl]sulfonyl-benzylamino]-3,5-dimethylbenzoic acid
• CAS: 306956-35-4
• 化学式: C₃₃H₃₀N₂O₇S
• 分子量: 598.676
• InChiKey: RIUQMHAKUJKOBC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.1
• 重原子数：
  43
• 可旋转键数：
  11
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  135
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  2-[[(4-{2-[(1-benzofuran-2-ylcarbonyl)amino]ethoxy}phenyl)sulfonyl](benzyl)amino]-3,5-dimethylbenzoic acid 在 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 盐酸羟胺 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 以58%的产率得到WAY-170523
  参考文献：
  名称：

  Structure-Based Design of a Novel, Potent, and Selective Inhibitor for MMP-13 Utilizing NMR Spectroscopy and Computer-Aided Molecular Design

  摘要：

  The high-resolution NMR solution structure of the catalytic fragment of human collagenase-3 (MMP-13) was used as a starting point for structure-based design of selective inhibitors for MMP-13. The major structural difference observed between the MMP structures is the relative size and shape of the S1' pocket where this pocket is significantly longer for MMP-13, nearly reaching the surface of the protein. On the basis of the extended nature of the MMP-13 S1' pocket an inhibitor potent and selective for MMP-13 was designed from an initial high throughput screening (HTS) lead. CL-82198 was identified as a weak (10 muM) inhibitor against MMP-13 while demonstrating no activity against MMP-1, MMP-9, or the related enzyme TACE. The drug-Like properties of CL-82198 made it an ideal candidate for optimization of enzyme potency and selectivity. On the basis of NMR binding studies, it was shown that inhibitor CL-82198 bound within the entire S1' pocket of MMP-13 which is the basis of its selectivity against MMP-1, MMP-9, and TACE. A strategy utilizing this information was devised for designing new inhibitors that showed enhanced selectivity toward MMP-13. Our design strategy combined the critical selectivity features of CL-82198 with the known potency features of a nonspecific MMP inhibitor (WAY-152177) to generate a potent and selective MMP-13 inhibitor (WAY-170523). WAY-170523 has an IC50 of 17 nM for MMP-13 and showed > 5800-, 56-, and >500-fold selectivity against MMP-1 MMP-9, and TACE, respectively.

  DOI：

  10.1021/ja001547g
• 作为产物：
  描述：

  苯并呋喃-2-羧酸 在 N-甲基吗啉 、 sodium hydride 、 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 4.67h， 生成 2-[[(4-{2-[(1-benzofuran-2-ylcarbonyl)amino]ethoxy}phenyl)sulfonyl](benzyl)amino]-3,5-dimethylbenzoic acid
  参考文献：
  名称：

  Structure-Based Design of a Novel, Potent, and Selective Inhibitor for MMP-13 Utilizing NMR Spectroscopy and Computer-Aided Molecular Design

  摘要：

  The high-resolution NMR solution structure of the catalytic fragment of human collagenase-3 (MMP-13) was used as a starting point for structure-based design of selective inhibitors for MMP-13. The major structural difference observed between the MMP structures is the relative size and shape of the S1' pocket where this pocket is significantly longer for MMP-13, nearly reaching the surface of the protein. On the basis of the extended nature of the MMP-13 S1' pocket an inhibitor potent and selective for MMP-13 was designed from an initial high throughput screening (HTS) lead. CL-82198 was identified as a weak (10 muM) inhibitor against MMP-13 while demonstrating no activity against MMP-1, MMP-9, or the related enzyme TACE. The drug-Like properties of CL-82198 made it an ideal candidate for optimization of enzyme potency and selectivity. On the basis of NMR binding studies, it was shown that inhibitor CL-82198 bound within the entire S1' pocket of MMP-13 which is the basis of its selectivity against MMP-1, MMP-9, and TACE. A strategy utilizing this information was devised for designing new inhibitors that showed enhanced selectivity toward MMP-13. Our design strategy combined the critical selectivity features of CL-82198 with the known potency features of a nonspecific MMP inhibitor (WAY-152177) to generate a potent and selective MMP-13 inhibitor (WAY-170523). WAY-170523 has an IC50 of 17 nM for MMP-13 and showed > 5800-, 56-, and >500-fold selectivity against MMP-1 MMP-9, and TACE, respectively.

  DOI：

  10.1021/ja001547g

文献信息

• PREPARATION AND USE OF ORTHO-SULFONAMIDO ARYL HYDROXAMIC ACIDS AS MATRIX METALLOPROTEINASE INHIBITORS
  申请人：American Home Products Corporation

  公开号：US20020169184A1

  公开（公告）日：2002-11-14

  Ortho-sulfonamido aryl hydroxamic acids are provided which are useful, inter alia, for the inhibition of matrix metalloproteinases and the treatment of conditions associated with overexpression of MMPs.

  提供了ortho-磺酰胺基芳香羟肟酸，这些酸在抑制基质金属蛋白酶和治疗与MMP过度表达相关的疾病方面非常有用。
• Preparation and use of ortho-sulfonamido aryl hydroxamic acids as matrix metalloproteinase inhibitors
  申请人：Nelson Christy Frances

  公开号：US20050085504A1

  公开（公告）日：2005-04-21

  Ortho-sulfonamido aryl hydroxamic acids are provided which are useful, inter alia, for the inhibition of matrix metalloproteinases and the treatment of conditions associated with overexpression of MMPs.

  提供了ortho-磺酰胺基芳香羟肟酸，这些化合物可用于抑制基质金属蛋白酶并治疗与MMPs过度表达相关的疾病。
• The preparation and use of ortho-sulfonamido arylhydroxamic acids as matrix metalloproteinase inhibitors
  申请人：Wyeth

  公开号：US20030035332A1

  公开（公告）日：2003-02-20

  Ortho-sulfonamido aryl hydroxamic acids are provided which are useful, inter alia, for the inhibition of matrix metalloproteinases and the treatment of conditions associated with overexpression of MMPs.

  提供了一种Ortho-磺酰胺基芳香羟肟酸，可用于抑制基质金属蛋白酶和治疗与MMP过度表达相关的病症。
• Preparation and use of ortho-sulfonamido arylhydroxamic acids as matrix metalloproteinase inhibitors
  申请人：Wyeth

  公开号：US06825352B2

  公开（公告）日：2004-11-30

  Ortho-sulfonamido aryl hydroxamic acids are provided which are useful, inter alia, for the inhibition of matrix metalloproteinases and the treatment of conditions associated with overexpression of MMPs.

  提供了一种有用的ortho-磺酰胺基芳香羟肟酸，可用于抑制基质金属蛋白酶和治疗与MMP过度表达相关的疾病。
• Structure-Based Design of a Novel, Potent, and Selective Inhibitor for MMP-13 Utilizing NMR Spectroscopy and Computer-Aided Molecular Design
  作者：James M. Chen、Frances C. Nelson、Jeremy I. Levin、Dominick Mobilio、Franklin J. Moy、Ramaswamy Nilakantan、Arie Zask、Robert Powers

  DOI：10.1021/ja001547g

  日期：2000.10.1

  The high-resolution NMR solution structure of the catalytic fragment of human collagenase-3 (MMP-13) was used as a starting point for structure-based design of selective inhibitors for MMP-13. The major structural difference observed between the MMP structures is the relative size and shape of the S1' pocket where this pocket is significantly longer for MMP-13, nearly reaching the surface of the protein. On the basis of the extended nature of the MMP-13 S1' pocket an inhibitor potent and selective for MMP-13 was designed from an initial high throughput screening (HTS) lead. CL-82198 was identified as a weak (10 muM) inhibitor against MMP-13 while demonstrating no activity against MMP-1, MMP-9, or the related enzyme TACE. The drug-Like properties of CL-82198 made it an ideal candidate for optimization of enzyme potency and selectivity. On the basis of NMR binding studies, it was shown that inhibitor CL-82198 bound within the entire S1' pocket of MMP-13 which is the basis of its selectivity against MMP-1, MMP-9, and TACE. A strategy utilizing this information was devised for designing new inhibitors that showed enhanced selectivity toward MMP-13. Our design strategy combined the critical selectivity features of CL-82198 with the known potency features of a nonspecific MMP inhibitor (WAY-152177) to generate a potent and selective MMP-13 inhibitor (WAY-170523). WAY-170523 has an IC50 of 17 nM for MMP-13 and showed > 5800-, 56-, and >500-fold selectivity against MMP-1 MMP-9, and TACE, respectively.