(1R,2R,3S,4R,5S)-4-(2-chloro-6-((R)-cyclopropylcyclobutylmethylamino)-9H-purin-9-yl)-2,3-O-(isopropylidene)bicyclo[3.1.0]hexane | 1399604-36-4

• 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-(2-chloro-6-((R)-cyclopropylcyclobutylmethylamino)-9H-purin-9-yl)-2,3-O-(isopropylidene)bicyclo[3.1.0]hexane
• 英文别名: 2-chloro-N-[(R)-cyclobutyl(cyclopropyl)methyl]-9-[(1R,2R,4S,5R,6S)-8,8-dimethyl-7,9-dioxatricyclo[4.3.0.02,4]nonan-5-yl]purin-6-amine
• CAS: 1399604-36-4
• 化学式: C₂₂H₂₈ClN₅O₂
• 分子量: 429.95
• InChiKey: YPWZPLMUEPPCRE-YRKZSDTESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  30
• 可旋转键数：
  5
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.77
• 拓扑面积：
  74.1
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (1R,2R,3S,4R,5S)-4-(2-chloro-6-((R)-cyclopropylcyclobutylmethylamino)-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 7.0h， 以74%的产率得到(1R,2R,3S,4R,5S)-4-(2-chloro-6-((R)-cyclopropylcyclobutylmethylamino)-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：

  2,6-dichloro-9-((3aR,3bR,4aS,5R,5aS)-2,2-dimethylhexahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-5-yl)-9H-purine 、 (R)-cyclopropylcyclobutylmethylamine hydrochloride 在 三乙胺 作用下， 以 甲醇 为溶剂， 以83%的产率得到(1R,2R,3S,4R,5S)-4-(2-chloro-6-((R)-cyclopropylcyclobutylmethylamino)-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

文献信息

• Structural Sweet Spot for A₁ Adenosine Receptor Activation by Truncated (N)-Methanocarba Nucleosides: Receptor Docking and Potent Anticonvulsant Activity
  作者：Dilip K. Tosh、Silvia Paoletta、Francesca Deflorian、Khai Phan、Steven M. Moss、Zhan-Guo Gao、Xiaohui Jiang、Kenneth A. Jacobson

  DOI：10.1021/jm300965a

  日期：2012.9.27

  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.