8-((4-(cyclopropanecarbonyl)piperazin-1-yl)methyl)-7-isopentyl-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione hydrogen chloride | 2080306-22-3

• 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: 8-((4-(cyclopropanecarbonyl)piperazin-1-yl)methyl)-7-isopentyl-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione hydrogen chloride
• 英文别名: NCT-501 (hydrochloride)；8-[[4-(cyclopropanecarbonyl)piperazin-1-yl]methyl]-1,3-dimethyl-7-(3-methylbutyl)purine-2,6-dione;hydrochloride
• CAS: 2080306-22-3
• 化学式: C₂₁H₃₂N₆O₃*ClH
• 分子量: 452.984
• InChiKey: MQNBJYUQFQUJQZ-UHFFFAOYSA-N

物化性质

• 溶解度：
  DMF：30mg/mL； DMSO：30mg/mL；乙醇：20mg/mL； PBS（pH 7.2）：10 mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  0.96
• 重原子数：
  31
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  82
• 氢给体数：
  1
• 氢受体数：
  5

制备方法与用途

生物活性

NCT-501 氢氯酸盐是一种有效的茶碱类选择性醛脱氢酶 1A1 (ALDH1A1) 抑制剂，当抑制 hALDH1A1 时其 IC50 值为 40 nM。它对其他 ALDH 同工酶和其它脱氢酶的选择性较高（在 hALDH1B1、hALDH3A1 和 hALDH2 中的 IC50 值均大于 57 μM）。

靶点

• IC50: 40 nM (hALDH1A1)

体外研究

在 Cal-27 CisR 细胞系中，NCT-501 在 20 nM 浓度下表现出 16% 的抑制作用，但差异无统计学意义。

体内研究

在 Cal-27 CisR 异种移植肿瘤模型中，以每两日一次的剂量 (100 µg/动物；i.t.) 连续给药 20 天后，NCT-501 显示出 78% 的肿瘤生长抑制作用。

反应信息

• 作为产物：
  描述：

  5,6-二氨基-1,3-二甲基脲嘧啶 在 盐酸 、 三乙酰氧基硼氢化钠 、 potassium carbonate 、 戴斯-马丁氧化剂 、 三乙胺 作用下， 以 1,4-二氧六环 、 正己烷 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 11.33h， 生成 8-((4-(cyclopropanecarbonyl)piperazin-1-yl)methyl)-7-isopentyl-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione hydrogen chloride
  参考文献：
  名称：

  Discovery of NCT-501, a Potent and Selective Theophylline-Based Inhibitor of Aldehyde Dehydrogenase 1A1 (ALDH1A1)

  摘要：

  Aldehyde dehydrogenases (ALDHs) metabolize reactive aldehydes and possess important physiological and toxicological functions in areas such as CNS, metabolic disorders, and cancers. Increased ALDH (e.g., ALDH1A1) gene expression and catalytic activity are vital biomarkers in a number of malignancies and cancer stem cells, highlighting the need for the identification and development of small molecule ALDH inhibitors. A new series of theophylline-based analogs as potent ALDH1A1 inhibitors is described. The optimization of hits identified from a quantitative high throughput screening (qHTS) campaign led to analogs with improved potency and early ADME properties. This chemotype exhibits highly selective inhibition against ALDH1A1 over ALDH3A1, ALDH1B1, and ALDH2 isozymes as well as other dehydrogenases such as HPGD and HSD17 beta 4. Moreover, the pharrnacokinetic evaluation of selected analog 64 (NCT-501) is also highlighted.

  DOI：

  10.1021/acs.jmedchem.5b00577

文献信息

• Discovery of NCT-501, a Potent and Selective Theophylline-Based Inhibitor of Aldehyde Dehydrogenase 1A1 (ALDH1A1)
  作者：Shyh-Ming Yang、Adam Yasgar、Bettina Miller、Madhu Lal-Nag、Kyle Brimacombe、Xin Hu、Hongmao Sun、Amy Wang、Xin Xu、Kimloan Nguyen、Udo Oppermann、Marc Ferrer、Vasilis Vasiliou、Anton Simeonov、Ajit Jadhav、David J. Maloney

  DOI：10.1021/acs.jmedchem.5b00577

  日期：2015.8.13

  Aldehyde dehydrogenases (ALDHs) metabolize reactive aldehydes and possess important physiological and toxicological functions in areas such as CNS, metabolic disorders, and cancers. Increased ALDH (e.g., ALDH1A1) gene expression and catalytic activity are vital biomarkers in a number of malignancies and cancer stem cells, highlighting the need for the identification and development of small molecule ALDH inhibitors. A new series of theophylline-based analogs as potent ALDH1A1 inhibitors is described. The optimization of hits identified from a quantitative high throughput screening (qHTS) campaign led to analogs with improved potency and early ADME properties. This chemotype exhibits highly selective inhibition against ALDH1A1 over ALDH3A1, ALDH1B1, and ALDH2 isozymes as well as other dehydrogenases such as HPGD and HSD17 beta 4. Moreover, the pharrnacokinetic evaluation of selected analog 64 (NCT-501) is also highlighted.