(1R,2R,3S,4R,5S)-4-(2-chloro-6-((R)-cyclopropylphenylmethylamino)-9H-purin-9-yl)bicyclo[3.1.0]hexane-2,3-diol | 1399604-22-8

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 核苷和核苷酸类似物
• 英文名称: (1R,2R,3S,4R,5S)-4-(2-chloro-6-((R)-cyclopropylphenylmethylamino)-9H-purin-9-yl)bicyclo[3.1.0]hexane-2,3-diol
• 英文别名: (1R,2R,3S,4R,5S)-4-[2-chloro-6-[[(R)-cyclopropyl(phenyl)methyl]amino]purin-9-yl]bicyclo[3.1.0]hexane-2,3-diol
• CAS: 1399604-22-8
• 化学式: C₂₁H₂₂ClN₅O₂
• 分子量: 411.891
• InChiKey: NSOKXABWNKYUGW-YRKZSDTESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  29
• 可旋转键数：
  5
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  96.1
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 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 在 三乙胺 作用下， 以 甲醇 、 水 为溶剂， 反应 7.0h， 生成 (1R,2R,3S,4R,5S)-4-(2-chloro-6-((R)-cyclopropylphenylmethylamino)-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

文献信息

• ADENOSINE RECEPTOR AGONISTS, PARTIAL AGONISTS, AND ANTAGONISTS
  申请人：Jacobson Kenneth A.

  公开号：US20120252823A1

  公开（公告）日：2012-10-04

  Disclosed are A 3 adenosine receptor antagonists and/or partial agonists and A 1 adenosine receptor agonists and/or partial agonists of formula (I): wherein R 1 to R 5 are as described herein, as well as pharmaceutical compositions thereof and methods of use thereof. The A 3 AR antagonists or partial agonists find use in treating a number of diseases such as cancer, glaucoma, and inflammatory diseases, as well as in preventing cardiac ischemia. Also disclosed are radiolabeled compounds of formula (I) and the use thereof in diagnostic imaging of tissues and organs. The A 1 AR agonists and partial agonists find use in treating diseases such as seizures, convulsion, stroke, diabetes, pain, arrhythmias, depression, and anxiety and in cardioprotection or neuroprotection.

  本发明涉及式(I)的A3腺苷受体拮抗剂和/或部分激动剂以及A1腺苷受体激动剂和/或部分激动剂，其中R1至R5如本文所述，以及其制药组合物和使用方法。A3AR拮抗剂或部分激动剂可用于治疗诸如癌症、青光眼和炎症性疾病等多种疾病，以及预防心脏缺血。本发明还涉及式(I)的放射性标记化合物及其在组织和器官的诊断成像中的应用。A1AR激动剂和部分激动剂可用于治疗癫痫、惊厥、中风、糖尿病、疼痛、心律失常、抑郁症和焦虑症以及心脏保护或神经保护。
• US9181253B2
  申请人：——

  公开号：US9181253B2

  公开（公告）日：2015-11-10
• 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.