(1'S,2'R,3'S,4'R,5'S)-4-(6-amino-2-chloropurin-9-yl)-1-[hydroxydeuteromethyl]-2,3-(O-isopropylidine)bicyclo[3.1.0]hexane

• 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: (1'S,2'R,3'S,4'R,5'S)-4-(6-amino-2-chloropurin-9-yl)-1-[hydroxydeuteromethyl]-2,3-(O-isopropylidine)bicyclo[3.1.0]hexane
• 英文别名: [(1R,2S,4S,5R,6S)-5-(6-amino-2-chloropurin-9-yl)-8,8-dimethyl-7,9-dioxatricyclo[4.3.0.02,4]nonan-2-yl]-dideuteriomethanol
• 化学式: C₁₅H₁₈ClN₅O₃
• 分子量: 353.777
• InChiKey: JGPIEHIXFNKRCS-DUMXRZDCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  24
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  108
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (1'S,2'R,3'S,4'R,5'S)-4-(6-amino-2-chloropurin-9-yl)-1-[hydroxydeuteromethyl]-2,3-(O-isopropylidine)bicyclo[3.1.0]hexane 在 吡啶 作用下， 以 甲醇 、 水 、 甲苯 为溶剂， 反应 10.0h， 生成 [[(1S,2R,3S,4R,5S)-4-(6-amino-2-chloropurin-9-yl)-2,3-dihydroxy-1-bicyclo[3.1.0]hexanyl]-dideuteriomethyl] diethyl phosphate
  参考文献：
  名称：

  5′-Phosphate and 5′-Phosphonate Ester Derivatives of (N)-Methanocarba Adenosine with in Vivo Cardioprotective Activity

  摘要：

  Activation of a cardiac myocyte P2X4 receptor protects against heart failure. 5'-Phosphonate and 5'-phosphate analogues of AMP containing a (N)-methanocarba (bicyclo[3.1.0]hexane) system could protect from heart failure by potentially activating this cardioprotective channel. Phosphoesters and phosphonodiesters were synthesized and administered in vivo via a miniosmotic pump in a mouse ischemic heart failure model and most significantly increased intact heart contractile function (echocardiography) compared to vehicle were protective in a calsequestrin (CSQ) overexpressing heart infusion. Several new thio and deuterated phosphate derivatives failure model. Diethyl (7, MRS4084) and diisopropyl (8, MRS4074) phosphotriesters were highly protective in the ischemic model. Substitution of 2-Cl with iodo reduced protection in the CSQ model. Diisopropyl ester 16 (MRS2978) of (1'S,2'R,3'S,4'R,5'S)-4'-(6-amino-2-chloropurin-9-yl)-2',3'-(dihydroxy)-1'-(phosphonoethylene)bicyclo[3.1.0]hexane was highly efficacious (CSQ), while lower homologue 1'-phosphonomethylene derivative 14 was inactive. Thus, we identified undiarged carbocyclic nucleotide analogues that represent potential candidates for the treatment of heart failure, suggesting this as a viable and structurally broad approach.

  DOI：

  10.1021/jm301372c
• 作为产物：
  描述：

  ethyl (1'S,2'R,3'S,4'R,5'S)-4-(6-amino-2-chloropurin-9-yl)-2,3-O-(isopropylidene)bicyclo[3.1.0]hexanecarboxylate 以 甲苯 为溶剂， 反应 4.0h， 以72%的产率得到(1'S,2'R,3'S,4'R,5'S)-4-(6-amino-2-chloropurin-9-yl)-1-[hydroxydeuteromethyl]-2,3-(O-isopropylidine)bicyclo[3.1.0]hexane
  参考文献：
  名称：

  5′-Phosphate and 5′-Phosphonate Ester Derivatives of (N)-Methanocarba Adenosine with in Vivo Cardioprotective Activity

  摘要：

  Activation of a cardiac myocyte P2X4 receptor protects against heart failure. 5'-Phosphonate and 5'-phosphate analogues of AMP containing a (N)-methanocarba (bicyclo[3.1.0]hexane) system could protect from heart failure by potentially activating this cardioprotective channel. Phosphoesters and phosphonodiesters were synthesized and administered in vivo via a miniosmotic pump in a mouse ischemic heart failure model and most significantly increased intact heart contractile function (echocardiography) compared to vehicle were protective in a calsequestrin (CSQ) overexpressing heart infusion. Several new thio and deuterated phosphate derivatives failure model. Diethyl (7, MRS4084) and diisopropyl (8, MRS4074) phosphotriesters were highly protective in the ischemic model. Substitution of 2-Cl with iodo reduced protection in the CSQ model. Diisopropyl ester 16 (MRS2978) of (1'S,2'R,3'S,4'R,5'S)-4'-(6-amino-2-chloropurin-9-yl)-2',3'-(dihydroxy)-1'-(phosphonoethylene)bicyclo[3.1.0]hexane was highly efficacious (CSQ), while lower homologue 1'-phosphonomethylene derivative 14 was inactive. Thus, we identified undiarged carbocyclic nucleotide analogues that represent potential candidates for the treatment of heart failure, suggesting this as a viable and structurally broad approach.

  DOI：

  10.1021/jm301372c

文献信息

• COMPOSITIONS AND METHODS TO TREAT CARDIAC DISEASES
  申请人：Liang Bruce

  公开号：US20110212924A1

  公开（公告）日：2011-09-01

  Phosphonate and phosphinate N-methanocarba derivatives of AMP including their prodrug analogs are described. MRS2339, a 2-chloro-AMP derivative containing a (N)-methanocarba (bicyclo[3.1.0]hexane) ring system in place of ribose, activates P2X receptors, ligand-gated ion channels. Phosphonate analogues of MRS2339 were synthesized using Michaelis-Arbuzov and Wittig reactions, based on the expectation of increased half-life in vivo due to the stability of the C—P bond. When administered to calsequestrin-overexpressing mice (a genetic model of heart failure) via a mini-osmotic pump (Alzet), some analogues significantly increased intact heart contractile function in vivo, as assessed by echocardiography-derived fractional shortening (FS) as compared to vehicle-infused mice. The range of carbocyclic nucleotide analogues for treatment of heart failure has been expanded.