8-cyclopentyl-7-oxo-2-[quinolin-8-ylamino]-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 8-cyclopentyl-7-oxo-2-[quinolin-8-ylamino]-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
• 化学式: C₂₂H₁₈N₆O
• 分子量: 382.425
• InChiKey: AXOSNHFEMCSFJW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.07
• 重原子数：
  29.0
• 可旋转键数：
  3.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  96.49
• 氢给体数：
  1.0
• 氢受体数：
  7.0

反应信息

• 作为产物：
  描述：

  4-氨基-2-甲巯基嘧啶-5-甲醛 在 sodium hydride 、 溶剂黄146 、 间氯过氧苯甲酸 、 苄胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 11.08h， 生成 8-cyclopentyl-7-oxo-2-[quinolin-8-ylamino]-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

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.