6-chloro-9H-(2-C-methyl-2,3-O-isopropylidene-β-D-ribofuranosyl)purine | 205171-13-7

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘌呤核苷
• 英文名称: 6-chloro-9H-(2-C-methyl-2,3-O-isopropylidene-β-D-ribofuranosyl)purine
• 英文别名: [(3aR,4R,6R,6aR)-4-(6-chloropurin-9-yl)-2,2,3a-trimethyl-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-6-yl]methanol
• CAS: 205171-13-7
• 化学式: C₁₄H₁₇ClN₄O₄
• 分子量: 340.766
• InChiKey: DQFYXAQULOHRQY-AMJCQUEASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  23
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  91.5
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  6-chloro-9H-(2-C-methyl-2,3-O-isopropylidene-β-D-ribofuranosyl)purine 在 chromium(VI) oxide 、 氯化亚砜 、 硫酸 、 三乙胺 作用下， 以 丙酮 、 乙腈 为溶剂， 反应 98.0h， 生成 (3aR,4S,6R,6aR)-6-[6-(3-Iodo-benzylamino)-purin-9-yl]-2,2,6a-trimethyl-tetrahydro-furo[3,4-d][1,3]dioxole-4-carboxylic acid ethyl ester
  参考文献：
  名称：

  2‘-C-Methyl Analogues of Selective Adenosine Receptor Agonists:  Synthesis and Binding Studies

  摘要：

  2'-C-Methyl analogues of selective adenosine receptor agonists such as (R)-PIA, CPA, CCPA, NECA, and IB-MECA were synthesized in order to further investigate the subdomain that binds the ribose moiety. Binding affinities of these new compounds at A(1) and A(2A) receptors in bovine brain membranes and at A(3) in rat testis membranes were determined and compared. It was found that the 2'-C-methyl modification resulted in a decrease of the affinity, particularly at A(2A) and A(3) receptors. When such modification was combined with N-6-substitutions with groups which induce high potency and selectivity at Al receptors, the high affinity was retained and the selectivity was increased. Thus, 2-chloro-2'-C-methyl-N-6-cyclopentyladenosine (2'-Me-CCPA), which displayed a K-i value of 1.8 nM at A(1) receptors, was selective for A(1) vs A(2A) and A(3) receptors by 2166- and 2777-fold, respectively, resulting in one of the most potent and A(1)-selective agonists so far known. In functional assay, this compound inhibited forskolin-stimulated adenylyl cyclase activity with an IC50 value of 13.1 nM, acting as a full agonist.

  DOI：

  10.1021/jm9707737
• 作为产物：
  描述：

  6-氯-9-(2,3,5-三苯甲酰氧基-2-C-甲基-beta-D-呋喃核糖基)-9H-嘌呤 在 氨 、 对甲苯磺酸 、 原甲酸三乙酯 作用下， 反应 10.0h， 生成 6-chloro-9H-(2-C-methyl-2,3-O-isopropylidene-β-D-ribofuranosyl)purine
  参考文献：
  名称：

  2‘-C-Methyl Analogues of Selective Adenosine Receptor Agonists:  Synthesis and Binding Studies

  摘要：

  2'-C-Methyl analogues of selective adenosine receptor agonists such as (R)-PIA, CPA, CCPA, NECA, and IB-MECA were synthesized in order to further investigate the subdomain that binds the ribose moiety. Binding affinities of these new compounds at A(1) and A(2A) receptors in bovine brain membranes and at A(3) in rat testis membranes were determined and compared. It was found that the 2'-C-methyl modification resulted in a decrease of the affinity, particularly at A(2A) and A(3) receptors. When such modification was combined with N-6-substitutions with groups which induce high potency and selectivity at Al receptors, the high affinity was retained and the selectivity was increased. Thus, 2-chloro-2'-C-methyl-N-6-cyclopentyladenosine (2'-Me-CCPA), which displayed a K-i value of 1.8 nM at A(1) receptors, was selective for A(1) vs A(2A) and A(3) receptors by 2166- and 2777-fold, respectively, resulting in one of the most potent and A(1)-selective agonists so far known. In functional assay, this compound inhibited forskolin-stimulated adenylyl cyclase activity with an IC50 value of 13.1 nM, acting as a full agonist.

  DOI：

  10.1021/jm9707737

文献信息

• [EN] SUBSTITUTED NUCLEOSIDE ANALOGUES FOR USE AS PRMT5 INHIBITORS<br/>[FR] ANALOGUES DE NUCLÉOSIDES SUBSTITUÉS DESTINÉS À ÊTRE UTILISÉS EN TANT QU'INHIBITEURS DE PRMT5
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2017153186A1

  公开（公告）日：2017-09-14

  The present invention relates novel substituted nucleoside analogues of Formula (I) wherein the variables have the meaning defined in the claims. The compounds according to the present invention are useful as PRMT5 inhibitors. The invention further relates to pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.

  本发明涉及式(I)的新型取代核苷类似物，其中变量具有如权利要求中所定义的含义。根据本发明的化合物作为PRMT5抑制剂是有用的。本发明进一步涉及包含所述化合物作为活性成分的药物组合物，以及将所述化合物用作药物的应用。
• SUBSTITUTED NUCLEOSIDE ANALOGUES FOR USE AS PRMT5 INHIBITORS
  申请人：Janssen Pharmaceutica NV

  公开号：EP3426664B1

  公开（公告）日：2021-06-30
• NOVEL SUBSTITUTED NUCLEOSIDE ANALOGUES FOR USE AS PRMT5 INHIBITORS
  申请人：Janssen Pharmaceutica NV

  公开号：US20200289539A1

  公开（公告）日：2020-09-17

  The present invention relates novel substituted nucleoside analogues of Formula (I) wherein the variables have the meaning defined in the claims. The compounds according to the present invention are useful as PRMT5 inhibitors. The invention further relates to pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.
• 2‘-<i>C</i>-Methyl Analogues of Selective Adenosine Receptor Agonists:  Synthesis and Binding Studies
  作者：Palmarisa Franchetti、Loredana Cappellacci、Stefano Marchetti、Letizia Trincavelli、Claudia Martini、Maria R. Mazzoni、Antonio Lucacchini、Mario Grifantini

  DOI：10.1021/jm9707737

  日期：1998.5.1

  2'-C-Methyl analogues of selective adenosine receptor agonists such as (R)-PIA, CPA, CCPA, NECA, and IB-MECA were synthesized in order to further investigate the subdomain that binds the ribose moiety. Binding affinities of these new compounds at A(1) and A(2A) receptors in bovine brain membranes and at A(3) in rat testis membranes were determined and compared. It was found that the 2'-C-methyl modification resulted in a decrease of the affinity, particularly at A(2A) and A(3) receptors. When such modification was combined with N-6-substitutions with groups which induce high potency and selectivity at Al receptors, the high affinity was retained and the selectivity was increased. Thus, 2-chloro-2'-C-methyl-N-6-cyclopentyladenosine (2'-Me-CCPA), which displayed a K-i value of 1.8 nM at A(1) receptors, was selective for A(1) vs A(2A) and A(3) receptors by 2166- and 2777-fold, respectively, resulting in one of the most potent and A(1)-selective agonists so far known. In functional assay, this compound inhibited forskolin-stimulated adenylyl cyclase activity with an IC50 value of 13.1 nM, acting as a full agonist.