N-{3-[9-Ethyl-2-(trans-4-hydroxy-cyclo-hexylamino)-9H-purin-6-yl-amino]-phenyl}-3-p-tolylpropargylic acid amide | 289479-94-3

• 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: N-{3-[9-Ethyl-2-(trans-4-hydroxy-cyclo-hexylamino)-9H-purin-6-yl-amino]-phenyl}-3-p-tolylpropargylic acid amide
• 英文别名: N-[3-({9-ethyl-2-[(trans-4-hydroxycyclohexyl)amino]-9H-purin-6-yl}amino)phenyl]-3-(4-methylphenyl)prop-2-ynamide
• CAS: 289479-94-3
• 化学式: C₂₉H₃₁N₇O₂
• 分子量: 509.611
• InChiKey: QPFYQTIUHLNNSI-SAIGFBBZSA-N

物化性质

• 密度：
  1.31±0.1 g/cm3(Predicted)
• 溶解度：
  DMSO：100 mg/mL (196.23 mM)；水：< 0.1 mg/mL（不溶）

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  38.0
• 可旋转键数：
  6.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  116.99
• 氢给体数：
  4.0
• 氢受体数：
  8.0

制备方法与用途

生物活性

TN1 是一种有效的胎儿型血红蛋白 (HbF) 诱导剂。

靶点

fetal hemoglobin (HbF)

体外研究

A high-throughput screen of a large chemical library identifies a 2,6-diamino-substituted purine, TN1, which induces fetal hemoglobin (HbF) more potently than hydroxyurea in KU812 and K562 leukemia cell lines.TN1 increases HbF protein in both leukemic KU812 and K562 cells in a dose-dependent manner. At 100 nM concentration, Western blot analysis indicated that TN1 increased γ-globin expression (2.9- and 3.7-fold increase in KU812 cell and K562 cell, respectively) to higher levels than 50-100 μM HU (1.8- and 1.9-fold increase in KU812 cell and K562 cell, respectively), the first drug approved for the treatment of SCD. The EC ₅₀ value for TN1-mediated HbF induction is approximately three orders of magnitude lower than that of HU (HU: EC ₅₀ =50-100 μM; TN1: EC ₅₀ =100 nM). In addition, TN1 is more potent than a number of previously reported small-molecule HbF inducers including sodium butyrate and other histone deacetylase (HDAC) inhibitors. At the concentrations tested, TN1, as well as hemin and HU, increase γ-globin mRNA transcription (greater than fourfold), indicating that TN1 increases γ-globin levels at both the transcriptional and protein level. The time course of TN1-induced γ-globin mRNA and protein synthesis is measured and both increase after approximately 24 h of treatment. TN1 also induces β-globin mRNA in addition to γ-globin mRNA, similar to hydroxyurea.

反应信息

• 作为产物：
  描述：

  (2-chloro-9-ethyl-9H-purin-6-yl)-(3-nitro-phenyl)-amine 在 盐酸 、 palladium 10% on activated carbon 、 氢气 、 三乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 甲醇 、 二乙二醇二甲醚 、 N,N-二甲基甲酰胺 为溶剂， 反应 48.0h， 生成 N-{3-[9-Ethyl-2-(trans-4-hydroxy-cyclo-hexylamino)-9H-purin-6-yl-amino]-phenyl}-3-p-tolylpropargylic acid amide
  参考文献：
  名称：

  Potent and orally active purine-based fetal hemoglobin inducers for treating β-thalassemia and sickle cell disease

  摘要：

  Reactivation of fetal hemoglobin (HbF) expression by therapeutic agents has been suggested as an alternative treatment to modulate anemia and the related symptoms of severe β-thalassemia and sickle cell disease (SCD). Hydroxyurea (HU) is the first US FDA-approved HbF inducer for treating SCD. However, approximately 25% of the patients with SCD do not respond to HU. A previous study identified TN1 (1) as a small-molecule HbF inducer. However, this study found that the poor potency and oral bioavailability of compound 1 limits the development of this inducer for clinical use. To develop drug-like compounds, further structure-activity relationship studies on the purine-based structure of 1 were conducted. Herein, we report our discovery of a more potent inducer, compound 13a, that can efficiently induce γ-globin gene expression at non-cytotoxic concentrations. The molecular mechanism of 13a, for the regulation HbF expression, was also investigated. In addition, we demonstrated that oral administration of 13a can ameliorate anemia and the related symptoms in SCD mice. The results of this study suggest that 13a can be further developed as a novel agent for treating hemoglobinopathies, such as β-thalassemia and SCD.

  DOI：

  10.1016/j.ejmech.2020.112938

文献信息

• 2-Amino-6-anilino-purines and their use as medicaments
  申请人：——

  公开号：US20020016329A1

  公开（公告）日：2002-02-07

  2-Amino-6-anilino-purine derivatives of the formula I 1 in which the symbols are as defined in claim 1, are described. These compounds inhibit p34 cdc2 /cyclin B cdc13 kinase and protein tyrosine kinase pp60 c-src and can be used for treatment of hyperproliferative diseases, for example tumor diseases, and diseases which respond to inhibition of the activity of protein tyrosine kinase pp60 c-src , in particular osteoporosis.

  公式I中定义的符号如权利要求书1中所定义的那样，描述了1的2-氨基-6-苯胺基嘌呤衍生物。这些化合物抑制p34 cdc2/cyclin B cdc13激酶和蛋白酪氨酸激酶pp60 c-src，并可用于治疗过度增殖性疾病，例如肿瘤疾病，以及对蛋白酪氨酸激酶pp60 c-src活性抑制有反应的疾病，特别是骨质疏松症。
• 2-AMINO-6-ANILINO-PURINES AND THEIR USE AS MEDICAMENTS
  申请人：Novartis AG

  公开号：EP1153024B1

  公开（公告）日：2004-04-28
• US6767906B2
  申请人：——

  公开号：US6767906B2

  公开（公告）日：2004-07-27