4-butylamino-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester | 1027417-40-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 4-butylamino-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester
• 英文别名: Ethyl 4-(butylamino)-2-methylsulfanylpyrimidine-5-carboxylate
• CAS: 1027417-40-8
• 化学式: C₁₂H₁₉N₃O₂S
• 分子量: 269.368
• InChiKey: RINQRWNDPTXJHH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  18
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  89.4
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-butylamino-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester 在 manganese(IV) oxide 、 lithium aluminium tetrahydride 、 溶剂黄146 、 苄胺 作用下， 以 四氢呋喃 、 氯仿 为溶剂， 反应 31.0h， 生成 8-butyl-2-methylsulfanyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
  参考文献：
  名称：

  Discovery of 8-Cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x) as a Potent Inhibitor of Cyclin-Dependent Kinase 4 (CDK4) and AMPK-Related Kinase 5 (ARK5)

  摘要：

  The success of imatinib, a BCR-ABL inhibitor for the treatment of chronic myelogenous leukemia, has created a great impetus for the development of additional kinase inhibitors as therapeutic agents. However, the complexity of cancer has led to recent interest in polypharmacological approaches for developing multikinase inhibitors with low toxicity profiles. With this goal in mind, we analyzed more than 150 novel cyano pyridopyrimidine compounds and identified structure-activity relationship trends that can be exploited in the design of potent kinase inhibitors. One compound, 8-cyclopentyl-2[-4-(4-methyl-piperazin-l-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x), was found to be the most active, inducing apoptosis of tumor cells at a concentration of approximately 30-100 nM. In vitro kinase profiling revealed that 7x is a multikinase inhibitor with potent inhibitory activity against the CDK4/CYCLIN D1 and ARKS kinases. Here, we report the synthesis, structure-activity relationship, kinase inhibitory profile, in vitro cytotoxicity, and in vivo tumor regression studies by this lead compound.

  DOI：

  10.1021/jm401073p
• 作为产物：
  描述：

  4-氯-2-甲硫基嘧啶-5-羧酸乙酯 、 正丁胺 在 三乙胺 作用下， 以 四氢呋喃 为溶剂， 生成 4-butylamino-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester
  参考文献：
  名称：

  治疗胰腺癌的新型NAE抑制剂的合理设计与开发

  摘要：

  由于缺乏有效的靶向治疗和高侵袭性，胰腺癌在临床上仍然具有挑战性。NEDD8 激活酶 (NAE) 在癌症的各种细胞功能中起着关键作用。在此，我们报告了一系列新的 pyrido[2,3-d]pyrimidin-7(8 H )-one 衍生物的合成、优化和评估，作为高选择性和有效的 NAE 抑制剂，能够快速降解相关底物和有效的抑制 BxPC-3 细胞增殖。此外，蛋白质印迹分析表明化合物51可以抑制 NAE 活性，导致 BxPC-3 细胞凋亡。此外，化合物51在体外诱导细胞凋亡并抑制 BxPC-3 异种移植模型中的肿瘤生长。我们的工作确定51是一种高效的 NAE 抑制剂，代表了一种有效的策略和作为胰腺癌新靶向治疗的巨大潜力。

  DOI：

  10.1007/s00044-022-02979-8

文献信息

• Discovery of 8-Cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-<i>d</i>]pyrimidine-6-carbonitrile (<b>7x</b>) as a Potent Inhibitor of Cyclin-Dependent Kinase 4 (CDK4) and AMPK-Related Kinase 5 (ARK5)
  作者：M. V. Ramana Reddy、Balireddy Akula、Stephen C. Cosenza、Saikrishna Athuluridivakar、Muralidhar R. Mallireddigari、Venkat R. Pallela、Vinay K. Billa、D. R. C. Venkata Subbaiah、E. Vijaya Bharathi、Rodrigo Vasquez-Del Carpio、Amol Padgaonkar、Stacey J. Baker、E. Premkumar Reddy

  DOI：10.1021/jm401073p

  日期：2014.2.13

  The success of imatinib, a BCR-ABL inhibitor for the treatment of chronic myelogenous leukemia, has created a great impetus for the development of additional kinase inhibitors as therapeutic agents. However, the complexity of cancer has led to recent interest in polypharmacological approaches for developing multikinase inhibitors with low toxicity profiles. With this goal in mind, we analyzed more than 150 novel cyano pyridopyrimidine compounds and identified structure-activity relationship trends that can be exploited in the design of potent kinase inhibitors. One compound, 8-cyclopentyl-2[-4-(4-methyl-piperazin-l-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x), was found to be the most active, inducing apoptosis of tumor cells at a concentration of approximately 30-100 nM. In vitro kinase profiling revealed that 7x is a multikinase inhibitor with potent inhibitory activity against the CDK4/CYCLIN D1 and ARKS kinases. Here, we report the synthesis, structure-activity relationship, kinase inhibitory profile, in vitro cytotoxicity, and in vivo tumor regression studies by this lead compound.
• Rational design and development of novel NAE inhibitors for the treatment of pancreatic cancer
  作者：Cheng Lu、Peng Lu、Lei Gong、Li-Juan Zhu、Yuanyuan An、Yubin Wang

  DOI：10.1007/s00044-022-02979-8

  日期：2023.3

  cancers. Herein, we report the synthesis, optimization, and evaluation of a new series of pyrido[2,3-d]pyrimidin-7(8H)-one derivative as highly selective and efficacious NAE inhibitors, enabling rapid degradation of related substrates and potent inhibition of BxPC-3 cell proliferation. Moreover, western blot assays demonstrated that compound 51 could inhibit NAE activity, resulting in apoptosis in BxPC-3

  由于缺乏有效的靶向治疗和高侵袭性，胰腺癌在临床上仍然具有挑战性。NEDD8 激活酶 (NAE) 在癌症的各种细胞功能中起着关键作用。在此，我们报告了一系列新的 pyrido[2,3-d]pyrimidin-7(8 H )-one 衍生物的合成、优化和评估，作为高选择性和有效的 NAE 抑制剂，能够快速降解相关底物和有效的抑制 BxPC-3 细胞增殖。此外，蛋白质印迹分析表明化合物51可以抑制 NAE 活性，导致 BxPC-3 细胞凋亡。此外，化合物51在体外诱导细胞凋亡并抑制 BxPC-3 异种移植模型中的肿瘤生长。我们的工作确定51是一种高效的 NAE 抑制剂，代表了一种有效的策略和作为胰腺癌新靶向治疗的巨大潜力。