(1R,2R,3S,4R,5S)-4-(6-(dicyclopropylmethylamino)-2-(1H-pyrazole-4-methyl carboxyl-yl)-9H-purin-9-yl)-2,3-O-(isopropylidene)-bicyclo[3.1.0]hexane | 1399604-60-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: (1R,2R,3S,4R,5S)-4-(6-(dicyclopropylmethylamino)-2-(1H-pyrazole-4-methyl carboxyl-yl)-9H-purin-9-yl)-2,3-O-(isopropylidene)-bicyclo[3.1.0]hexane
• 英文别名: methyl 1-[6-(dicyclopropylmethylamino)-9-[(1R,2R,4S,5R,6S)-8,8-dimethyl-7,9-dioxatricyclo[4.3.0.02,4]nonan-5-yl]purin-2-yl]pyrazole-4-carboxylate
• CAS: 1399604-60-4
• 化学式: C₂₆H₃₁N₇O₄
• 分子量: 505.577
• InChiKey: VGSRWMUTQYVBIW-ADDNLYQESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  37
• 可旋转键数：
  8
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  118
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  (1R,2R,3S,4R,5S)-4-(6-(dicyclopropylmethylamino)-2-(1H-pyrazole-4-methyl carboxyl-yl)-9H-purin-9-yl)-2,3-O-(isopropylidene)-bicyclo[3.1.0]hexane 在 Dowex 50 resin 作用下， 以 甲醇 、 水 为溶剂， 反应 6.0h， 以77%的产率得到(1R,2R,3S,4R,5S)-4-(6-(dicyclopropylmethylamino)-2-(1H-pyrazole-4-methyl carboxyl-yl)-9H-purin-9-yl)bicyclo[3.1.0]hexane-2,3-diol
  参考文献：
  名称：

  Structural Sweet Spot for A₁ Adenosine Receptor Activation by Truncated (N)-Methanocarba Nucleosides: Receptor Docking and Potent Anticonvulsant Activity

  摘要：

  A(1) adenosine receptor (AR) agonists display antiischemic and antiepileptic neuroprotective activity, but peripheral cardiovascular side effects impeded their development. SAR study of N-6-cycloalkylmethyl 4'-truncated (N)-methanocarba-adenosines identified 10 (MRS5474, N-6-dicyclopropylmethyl, K-i = 47.9 nM) as a moderately A(1)AR-selective full agonist. Two stereochemically defined N-6-methynyl group substituents displayed narrow SAR; groups larger than cyclobutyl greatly reduced AR affinity, and those larger or smaller than cyclopropyl reduced A(1)AR selectivity. Nucleoside docking to A(1)AR homology model characterized distinct hydrophobic cyclopropyl subpockets, the larger "A" forming contacts with Thr270 (7.35), Tyr271 (7.36), Ile274 (7.39), and carbon chains of glutamates (EL2) and the smaller subpocket "B" forming contacts between TM6 and TM7. 10 suppressed minimal clonic seizures (6 Hz mouse model) without typical rotarod impairment of A(1)AR agonists. Truncated nucleosides, an appealing preclinical approach, have more druglike physicochemical properties than other A(1)AR agonists. Thus, we identified highly restricted regions for substitution around N-6 suitable for an A(1)AR agonist with anticonvulsant activity.

  DOI：

  10.1021/jm300965a
• 作为产物：
  描述：

  二甲酰基乙酸甲酯 、 (1R,2R,3S,4R,5S)-4-(6-(dicyclopropylmethylamino)-2-hydrazinyl-9H-purin-9-yl)-2,3-O-(isopropylidene)-bicyclo[3.1.0]hexane 以 乙醇 为溶剂， 反应 1.0h， 以84%的产率得到(1R,2R,3S,4R,5S)-4-(6-(dicyclopropylmethylamino)-2-(1H-pyrazole-4-methyl carboxyl-yl)-9H-purin-9-yl)-2,3-O-(isopropylidene)-bicyclo[3.1.0]hexane
  参考文献：
  名称：

  Structural Sweet Spot for A₁ Adenosine Receptor Activation by Truncated (N)-Methanocarba Nucleosides: Receptor Docking and Potent Anticonvulsant Activity

  摘要：

  A(1) adenosine receptor (AR) agonists display antiischemic and antiepileptic neuroprotective activity, but peripheral cardiovascular side effects impeded their development. SAR study of N-6-cycloalkylmethyl 4'-truncated (N)-methanocarba-adenosines identified 10 (MRS5474, N-6-dicyclopropylmethyl, K-i = 47.9 nM) as a moderately A(1)AR-selective full agonist. Two stereochemically defined N-6-methynyl group substituents displayed narrow SAR; groups larger than cyclobutyl greatly reduced AR affinity, and those larger or smaller than cyclopropyl reduced A(1)AR selectivity. Nucleoside docking to A(1)AR homology model characterized distinct hydrophobic cyclopropyl subpockets, the larger "A" forming contacts with Thr270 (7.35), Tyr271 (7.36), Ile274 (7.39), and carbon chains of glutamates (EL2) and the smaller subpocket "B" forming contacts between TM6 and TM7. 10 suppressed minimal clonic seizures (6 Hz mouse model) without typical rotarod impairment of A(1)AR agonists. Truncated nucleosides, an appealing preclinical approach, have more druglike physicochemical properties than other A(1)AR agonists. Thus, we identified highly restricted regions for substitution around N-6 suitable for an A(1)AR agonist with anticonvulsant activity.

  DOI：

  10.1021/jm300965a