5-(3-Morpholin-4-yl-propylsulfanyl)-1-phenyl-1H-benzoimidazole

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: 5-(3-Morpholin-4-yl-propylsulfanyl)-1-phenyl-1H-benzoimidazole
• 英文别名: 5-Substituted 1-Phenylbenzimidazole 25；4-[3-(1-phenylbenzimidazol-5-yl)sulfanylpropyl]morpholine
• 化学式: C₂₀H₂₃N₃OS
• 分子量: 353.488
• InChiKey: HCFYTLOODORVLY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  25
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  55.6
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  5-<(3-hydroxypropyl)thio>-1-phenylbenzimidazole 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 0.67h， 生成 5-(3-Morpholin-4-yl-propylsulfanyl)-1-phenyl-1H-benzoimidazole
  参考文献：
  名称：

  Structure−Activity Relationships for 5-Substituted 1-Phenylbenzimidazoles as Selective Inhibitors of the Platelet-Derived Growth Factor Receptor

  摘要：

  Following an earlier discovery of 1-phenylbenzimidazoles as ATP-site inhibitors of the platelet-derived growth factor receptor (PDGFR), further structure-activity relationships for analogues (particularly 5-substituted derivatives) are reported. The data are consistent with a binding model (constructed from the homology-modeled structure of the catalytic subunit of the PDGFR using protein kinase A as the template) in which the ligand binds in the relatively narrow ATP site, with the phenyl ring pointing toward the interior of the pocket and the 5-position of the benzimidazole ring toward the mouth of the pocket. The narrow binding pocket allows a maximum torsion angle between the phenyl and benzimidazole rings of about 40 degrees, consistent with that calculated (43.6 degrees) for the minimum-energy conformation of the unsubstituted free ligand. The inactivity of 7- or 2'-substituted analogues is consistent with the greater torsion angle (and thus larger ligand cross-section) of such substituted analogues. There is substantial bulk tolerance for 5-substituents, which protrude out of the mouth of the hydrophobic pocket, with the most effective analogues being those bearing weak bases. On the basis of this model, 5-OR derivatives bearing cationic side chains were prepared as soluble analogues, and these showed sub-micromolar potencies against the isolated PDGFR enzyme. They were also moderately effective inhibitors of autophosphorylation of PDGFR in rat aortic vascular smooth muscle cells, with IC(50)s in the range 0.1-1 mu 1M.

  DOI：

  10.1021/jm980658b

文献信息

• Structure−Activity Relationships for 5-Substituted 1-Phenylbenzimidazoles as Selective Inhibitors of the Platelet-Derived Growth Factor Receptor
  作者：Brian D. Palmer、Alan J. Kraker、Brian G. Hartl、Athanasia D. Panopoulos、Robert L. Panek、Brian L. Batley、Gina H. Lu、Susanne Trumpp-Kallmeyer、H. D. Hollis Showalter、William A. Denny

  DOI：10.1021/jm980658b

  日期：1999.7.1

  Following an earlier discovery of 1-phenylbenzimidazoles as ATP-site inhibitors of the platelet-derived growth factor receptor (PDGFR), further structure-activity relationships for analogues (particularly 5-substituted derivatives) are reported. The data are consistent with a binding model (constructed from the homology-modeled structure of the catalytic subunit of the PDGFR using protein kinase A as the template) in which the ligand binds in the relatively narrow ATP site, with the phenyl ring pointing toward the interior of the pocket and the 5-position of the benzimidazole ring toward the mouth of the pocket. The narrow binding pocket allows a maximum torsion angle between the phenyl and benzimidazole rings of about 40 degrees, consistent with that calculated (43.6 degrees) for the minimum-energy conformation of the unsubstituted free ligand. The inactivity of 7- or 2'-substituted analogues is consistent with the greater torsion angle (and thus larger ligand cross-section) of such substituted analogues. There is substantial bulk tolerance for 5-substituents, which protrude out of the mouth of the hydrophobic pocket, with the most effective analogues being those bearing weak bases. On the basis of this model, 5-OR derivatives bearing cationic side chains were prepared as soluble analogues, and these showed sub-micromolar potencies against the isolated PDGFR enzyme. They were also moderately effective inhibitors of autophosphorylation of PDGFR in rat aortic vascular smooth muscle cells, with IC(50)s in the range 0.1-1 mu 1M.