(3R)-2-(benzenesulfonyl)-3,4-dihydro-1H-isoquinoline-3-carboxylic acid

• 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)-2-(benzenesulfonyl)-3,4-dihydro-1H-isoquinoline-3-carboxylic acid
• 化学式: C₁₆H₁₅NO₄S
• 分子量: 317.365
• InChiKey: YBNFARCMGBPBOI-OAHLLOKOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  83.1
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (3R)-2-(benzenesulfonyl)-3,4-dihydro-1H-isoquinoline-3-carboxylic acid 在 N-乙基马来酰亚胺 、 氯甲酸乙酯 、 O-(三甲基硅)羟胺 作用下， 以 四氢呋喃 为溶剂， 生成 2-Benzenesulfonyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid hydroxyamide
  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)-(+)-1,2,3,4-四氢异喹啉-3-羧酸 、 苯磺酰氯 在 organic base 作用下， 以 1,4-二氧六环 、 水 为溶剂， 生成 (3R)-2-(benzenesulfonyl)-3,4-dihydro-1H-isoquinoline-3-carboxylic acid
  参考文献：
  名称：

  肝素结合表皮生长因子脱落抑制剂的三维定量构效关系研究使用比较分子场分析。

  摘要：

  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）=

  DOI：

  10.1021/jm0110385