4-(1-甲基-7-氧代-3-丙基-6,7-二氢-1H-吡唑并[4,3-d]嘧啶-5-基)噻吩-2-磺酰胺 | 1033852-63-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡唑并嘧啶类
• 中文名称: 4-(1-甲基-7-氧代-3-丙基-6,7-二氢-1H-吡唑并[4,3-d]嘧啶-5-基)噻吩-2-磺酰胺
• 英文名称: 5-(5-(aminosulfonyl)-3-thienyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one
• 英文别名: 4-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)thiophene-2-sulfonamide；4-(1-methyl-7-oxo-3-propyl-6H-pyrazolo[4,3-d]pyrimidin-5-yl)thiophene-2-sulfonamide
• CAS: 1033852-63-9
• 化学式: C₁₃H₁₅N₅O₃S₂
• 分子量: 353.426
• InChiKey: HBVPLRNDYLCQTI-UHFFFAOYSA-N

物化性质

• 沸点：
  630.8±65.0 °C(Predicted)
• 密度：
  1.69±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  156
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  4-(1-甲基-7-氧代-3-丙基-6,7-二氢-1H-吡唑并[4,3-d]嘧啶-5-基)噻吩-2-磺酰胺 、 氯甲酸丁酯 在 4-二甲氨基吡啶 作用下， 以 吡啶 为溶剂， 以61%的产率得到4-(1-甲基-7-氧代-3-丙基-6,7-二氢-1H-吡唑并[4,3-d]嘧啶-5-基)噻吩-2-基磺酰基氨基甲酸丁酯
  参考文献：
  名称：

  An insight into the pharmacophores of phosphodiesterase-5 inhibitors from synthetic and crystal structural studies

  摘要：

  Selective inhibitors of cyclic nucleotide phosphodiesterase-5 (PDE5) have been used as drugs for treatment of male erectile dysfunction and pulmonary hypertension. An insight into the pharmacophores of PDE5 inhibitors is essential for development of second generation of PDE5 inhibitors, but has not been completely illustrated. Here we report the synthesis of a new class of the sildenafil derivatives and a crystal structure of the PDES catalytic domain in complex with 5-(2-ethoxy-5-(sulfamoyl)-3-thienyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (12). Inhibitor 12 induces conformational change of the H-loop (residues 660-683), which is different from any of the known PDES structures. The pyrazolopyrimidinone groups of 12 and sildenafil are well superimposed, but their sulfonamide groups show a positional difference of as much as 1.5 angstrom. The structure-activity analysis suggests that a small hydrophobic pocket and the H-loop of PDE5 are important for the inhibitor affinity, in addition to two common elements for binding of almost all the PDE inhibitors: the stack against the phenylalanine and the hydrogen bond with the invariant glutamine. However, the PDE5-12 structure does not provide a full explanation to affinity changes of the inhibitors. Thus alternatives such as conformational change of the M-loop are open and further structural study is required. (C) 2008 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.bcp.2008.01.019
• 作为产物：
  描述：

  5-溴-4-(1-甲基-7-氧代-3-丙基-6,7-二氢-1H-吡唑并[4,3-d]嘧啶-5-基)噻吩-2-磺酰胺 在 锌 甲酸 作用下， 以 甲醇 为溶剂， 以82%的产率得到4-(1-甲基-7-氧代-3-丙基-6,7-二氢-1H-吡唑并[4,3-d]嘧啶-5-基)噻吩-2-磺酰胺
  参考文献：
  名称：

  An insight into the pharmacophores of phosphodiesterase-5 inhibitors from synthetic and crystal structural studies

  摘要：

  Selective inhibitors of cyclic nucleotide phosphodiesterase-5 (PDE5) have been used as drugs for treatment of male erectile dysfunction and pulmonary hypertension. An insight into the pharmacophores of PDE5 inhibitors is essential for development of second generation of PDE5 inhibitors, but has not been completely illustrated. Here we report the synthesis of a new class of the sildenafil derivatives and a crystal structure of the PDES catalytic domain in complex with 5-(2-ethoxy-5-(sulfamoyl)-3-thienyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (12). Inhibitor 12 induces conformational change of the H-loop (residues 660-683), which is different from any of the known PDES structures. The pyrazolopyrimidinone groups of 12 and sildenafil are well superimposed, but their sulfonamide groups show a positional difference of as much as 1.5 angstrom. The structure-activity analysis suggests that a small hydrophobic pocket and the H-loop of PDE5 are important for the inhibitor affinity, in addition to two common elements for binding of almost all the PDE inhibitors: the stack against the phenylalanine and the hydrogen bond with the invariant glutamine. However, the PDE5-12 structure does not provide a full explanation to affinity changes of the inhibitors. Thus alternatives such as conformational change of the M-loop are open and further structural study is required. (C) 2008 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.bcp.2008.01.019