(3R)-7-amino-2-(4-methoxyphenyl)sulfonyl-3,4-dihydro-1H-isoquinoline-3-carboxylic acid | 236403-46-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 四氢异喹啉
• 英文名称: (3R)-7-amino-2-(4-methoxyphenyl)sulfonyl-3,4-dihydro-1H-isoquinoline-3-carboxylic acid
• CAS: 236403-46-6
• 化学式: C₁₇H₁₈N₂O₅S
• 分子量: 362.406
• InChiKey: IWSRFPLJDFVRGD-MRXNPFEDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  118
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  二碳酸二叔丁酯 、 (3R)-7-amino-2-(4-methoxyphenyl)sulfonyl-3,4-dihydro-1H-isoquinoline-3-carboxylic acid 以 1,4-二氧六环 、 水 为溶剂， 生成 (R)-2-(4-methoxybenzenesulfonyl)-7-[(tert-butoxycarbonyl)amino]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
  参考文献：
  名称：

  Tetrahydroisoquinoline-3-carboxylate based matrix-metalloproteinase inhibitors: design, synthesis and structure–activity relationship

  摘要：

  The design, synthesis and structure-activity relationship (SAR) of a series of nonpeptidic 2-arylsulfonyl-1,2,3,4-tetra-hydro-isoquinoline-3-carboxylates and-hydroxamates as inhibitors of the matrix metalloproteinase human neutrophil collagenase (MMP-8) is described here. Based on available X-ray structures of MMP-8/inhibitor complexes, our structure-based design strategy was directed to complement major protein-ligand interaction regions mainly in the S1' hydrophobic specificity pocket close to the catalytic zinc ion. Here, the rigid 1,2,3,4-tetrahydroisoquinoline scaffold (Tic) provides ideal geometry to combine hydroxamates and carboxylates as typical zinc complexing functionalities, with a broad variety of S1' directed mono- and biaryl substituents consisting of aromatic rings perfectly accommodated within this more hydrophobic region of the MMP-8 inhibitor binding site. The effect of different S1' directed substituents, zinc-complexing groups, chirality and variations of the tetrahydroisoquinoline ring-system is investigated by systematic studies. X-ray structure analyses in combination with 3D-QSAR studies provided an additional understanding of key determinants for MMP-8 affinity in this series. The hypothetical binding mode for a typical molecule as basis for our inhibitor design was found in good agreement with a 1.7 Angstrom X-ray structure of this candidate in complex with the catalytic domain of human MMP-8. After analysis of all systematic variations, 3D-QSAR and X-ray structure analysis, novel S1' directed substituents were designed and synthesized and biologically evaluated. This finally results in inhibitors, which do not only show high biological affinity for MMP-8, but also exhibit good oral bioavailability in several animal species. (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(02)00215-8
• 作为产物：
  描述：

  (R)-2-(4-methoxybenzenesulfonyl)-7-[(tert-butoxycarbonyl)amino]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 在 N-甲基吗啉 、 盐酸 作用下， 以 四氢呋喃 、 乙醚 为溶剂， 反应 4.25h， 生成 (3R)-7-amino-2-(4-methoxyphenyl)sulfonyl-3,4-dihydro-1H-isoquinoline-3-carboxylic acid
  参考文献：
  名称：

  Tetrahydroisoquinoline-3-carboxylate based matrix-metalloproteinase inhibitors: design, synthesis and structure–activity relationship

  摘要：

  The design, synthesis and structure-activity relationship (SAR) of a series of nonpeptidic 2-arylsulfonyl-1,2,3,4-tetra-hydro-isoquinoline-3-carboxylates and-hydroxamates as inhibitors of the matrix metalloproteinase human neutrophil collagenase (MMP-8) is described here. Based on available X-ray structures of MMP-8/inhibitor complexes, our structure-based design strategy was directed to complement major protein-ligand interaction regions mainly in the S1' hydrophobic specificity pocket close to the catalytic zinc ion. Here, the rigid 1,2,3,4-tetrahydroisoquinoline scaffold (Tic) provides ideal geometry to combine hydroxamates and carboxylates as typical zinc complexing functionalities, with a broad variety of S1' directed mono- and biaryl substituents consisting of aromatic rings perfectly accommodated within this more hydrophobic region of the MMP-8 inhibitor binding site. The effect of different S1' directed substituents, zinc-complexing groups, chirality and variations of the tetrahydroisoquinoline ring-system is investigated by systematic studies. X-ray structure analyses in combination with 3D-QSAR studies provided an additional understanding of key determinants for MMP-8 affinity in this series. The hypothetical binding mode for a typical molecule as basis for our inhibitor design was found in good agreement with a 1.7 Angstrom X-ray structure of this candidate in complex with the catalytic domain of human MMP-8. After analysis of all systematic variations, 3D-QSAR and X-ray structure analysis, novel S1' directed substituents were designed and synthesized and biologically evaluated. This finally results in inhibitors, which do not only show high biological affinity for MMP-8, but also exhibit good oral bioavailability in several animal species. (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(02)00215-8

文献信息

• A Three-Dimensional Quantitative Structure−Activity Relationship Study of Heparin-Binding Epidermal Growth Factor Shedding Inhibitors Using Comparative Molecular Field Analysis
  作者：Roberta Bursi、Masaaki Sawa、Yasuyuki Hiramatsu、Hirosato Kondo

  DOI：10.1021/jm0110385

  日期：2002.2.1

  Despite the lack of structural information on the heparin-binding (HB) epidermal growth factor (EGF) shedding putative target enzyme, the design of potent HB-EGF shedding inhibitors has been attempted by means of comparative molecular field analysis (CoMFA), a well-established 3D-QSAR technique. Two different binding modes, obtained by docking a flexible representative into the MMP-3 and TACE target

  尽管缺乏关于肝素结合（HB）表皮生长因子（EGF）脱落假定靶酶的结构信息，但已经通过比较分子场分析（CoMFA）尝试了有效的HB-EGF脱落抑制剂的设计。建立的3D-QSAR技术。通过将柔性代表与MMP-3和TACE靶酶对接而获得的两种不同结合模式，被视为50种HB-EGF脱落抑制剂内部数据集的比对规则。CoMFA模型是使用标准的空间，静电以及Bohacek和McMartin的H键分子场得出的。这些字段被单独或组合使用。对于这两种比对，仅氢键场就产生了最佳的统计模型。通过对CoMFA轮廓的分析，可以得出测试S1'尺寸的想法 提出了一些新的抑制剂的建议，提出了四种抑制剂的合成和测试方法。事实证明，四种化合物中的三种具有良好的抑制活性（IC（50）= 0.56和0.60 microM）至出色的（IC（50）= 0.13 microM）。结合后，R（1）苯环附近的S1'口袋必须变窄的假说已由第四种化合物的弱活性（IC（50）=
• Tetrahydroisoquinoline-3-carboxylate based matrix-metalloproteinase inhibitors: design, synthesis and structure–activity relationship
  作者：Hans Matter、Manfred Schudok、Wilfried Schwab、Werner Thorwart、Denis Barbier、Günter Billen、Burkhard Haase、Bernhard Neises、Klaus-Ulrich Weithmann、Theo Wollmann

  DOI：10.1016/s0968-0896(02)00215-8

  日期：2002.11

  The design, synthesis and structure-activity relationship (SAR) of a series of nonpeptidic 2-arylsulfonyl-1,2,3,4-tetra-hydro-isoquinoline-3-carboxylates and-hydroxamates as inhibitors of the matrix metalloproteinase human neutrophil collagenase (MMP-8) is described here. Based on available X-ray structures of MMP-8/inhibitor complexes, our structure-based design strategy was directed to complement major protein-ligand interaction regions mainly in the S1' hydrophobic specificity pocket close to the catalytic zinc ion. Here, the rigid 1,2,3,4-tetrahydroisoquinoline scaffold (Tic) provides ideal geometry to combine hydroxamates and carboxylates as typical zinc complexing functionalities, with a broad variety of S1' directed mono- and biaryl substituents consisting of aromatic rings perfectly accommodated within this more hydrophobic region of the MMP-8 inhibitor binding site. The effect of different S1' directed substituents, zinc-complexing groups, chirality and variations of the tetrahydroisoquinoline ring-system is investigated by systematic studies. X-ray structure analyses in combination with 3D-QSAR studies provided an additional understanding of key determinants for MMP-8 affinity in this series. The hypothetical binding mode for a typical molecule as basis for our inhibitor design was found in good agreement with a 1.7 Angstrom X-ray structure of this candidate in complex with the catalytic domain of human MMP-8. After analysis of all systematic variations, 3D-QSAR and X-ray structure analysis, novel S1' directed substituents were designed and synthesized and biologically evaluated. This finally results in inhibitors, which do not only show high biological affinity for MMP-8, but also exhibit good oral bioavailability in several animal species. (C) 2002 Elsevier Science Ltd. All rights reserved.