(1R,2R,3S,4R,5S)-4-(2-chloro-6-(dicyclopropylmethylamino)-9H-purin-9-yl)-2',3'-O-(isopropylidene)-bicyclo[3.1.0]hexane | 1312015-44-3

• 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-(dicyclopropylmethylamino)-9H-purin-9-yl)-2',3'-O-(isopropylidene)-bicyclo[3.1.0]hexane
• CAS: 1312015-44-3
• 化学式: C₂₁H₂₆ClN₅O₂
• 分子量: 415.923
• InChiKey: REOWQUHTNRLTHL-GHVWTTSJSA-N

物化性质

• 沸点：
  546.5±60.0 °C(Predicted)
• 密度：
  1.83±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.79
• 重原子数：
  29.0
• 可旋转键数：
  5.0
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.76
• 拓扑面积：
  74.09
• 氢给体数：
  1.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  (1R,2R,3S,4R,5S)-4-(2-chloro-6-(dicyclopropylmethylamino)-9H-purin-9-yl)-2',3'-O-(isopropylidene)-bicyclo[3.1.0]hexane 在 一水合肼 、 sodium hydroxide 作用下， 以 甲醇 、 乙醇 、 水 为溶剂， 反应 13.0h， 生成 (1R,2R,3S,4R,5S)-4-(6-(dicyclopropylmethylamino)-2-(1H-pyrazole-4-carboxyl-yl)-9H-purin-9-yl)bicycle [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：

  (3aR,3bR,4aS,5S,5aS)-2,2-dimethylhexahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-5-ol 在 偶氮二甲酸二异丙酯 、 三乙胺 、 三苯基膦 作用下， 以 四氢呋喃 、 异丙醇 为溶剂， 反应 52.17h， 生成 (1R,2R,3S,4R,5S)-4-(2-chloro-6-(dicyclopropylmethylamino)-9H-purin-9-yl)-2',3'-O-(isopropylidene)-bicyclo[3.1.0]hexane
  参考文献：
  名称：

  [EN] COMPOUNDS AND METHODS FOR MODULATION OF G-PROTEIN-COUPLED RECEPTORS
  [FR] COMPOSÉS ET PROCÉDÉS DE MODULATION DE RÉCEPTEURS COUPLÉS À LA PROTÉINE G

  摘要：

  公开号：

  WO2019232554A3

文献信息

• Truncated (N)-Methanocarba Nucleosides as A₁ Adenosine Receptor Agonists and Partial Agonists: Overcoming Lack of a Recognition Element
  作者：Dilip K. Tosh、Khai Phan、Francesca Deflorian、Qiang Wei、Zhan-Guo Gao、Kenneth A. Jacobson

  DOI：10.1021/ml200114q

  日期：2011.8.11

  A(1) adenosine receptor (AR) agonists are neuroprotective, cardioprotective, and anxiolytic. (N)-Methanocarba adenine nucleosides designed to bind to human A(1)AR were truncated to eliminate 5'-CH2OH. This modification previously converted A(3)AR agonists into antagonists, but the comparable effect at A(1)AR is unknown. In comparison to ribosides, affinity at the A(1)AR was less well preserved than that at the A(3)AR, although a few derivatives were moderately A(1)AR selective, notably full agonist 21 (N-6-dicyclopropyl-methyl, K-i 47.9 nM). Thus, at the A(1)AR, recognition elements for nucleoside binding depend more on 5' region interactions, and in their absence, A(3)AR selectivity predominates. Based on the recently reported agonist-bound AR structure, this difference between subtypes likely correlates with an essential His residue in transmembrane domain 6 of A(1) but not A(3)AR The derivatives ranged from partial to full agonists in A(1)AR-mediated adenylate cyclase inhibition. Truncated derivatives have more druglike physical properties than other A(1)AR agonists; this approach is appealing for preclinical development.