(4-amino-2-ethylsulfanylpyrimidin-5-yl)(4-fluoro-2-methoxyphenyl)methanone | 741714-05-6

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (4-amino-2-ethylsulfanylpyrimidin-5-yl)(4-fluoro-2-methoxyphenyl)methanone
• 英文别名: (4-Amino-2-ethylsulfanylpyrimidin-5-yl)-(4-fluoro-2-methoxyphenyl)methanone
• CAS: 741714-05-6
• 化学式: C₁₄H₁₄FN₃O₂S
• 分子量: 307.348
• InChiKey: SFEHERISWPVTAK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  21
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  103
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  1-甲磺酰基-4-氨基哌啶 、 (4-amino-2-ethylsulfanylpyrimidin-5-yl)(4-fluoro-2-methoxyphenyl)methanone 在 间氯过氧苯甲酸 作用下， 以 氯仿 、 异丙醇 为溶剂， 反应 2.0h， 生成 [4-Amino-2-(1-methanesulfonylpiperidin-4-ylamino)pyrimidin-5-yl](4-fluoro-2-methoxyphenyl)methanone
  参考文献：
  名称：

  Discovery of [4-Amino-2-(1-methanesulfonylpiperidin-4-ylamino)pyrimidin-5-yl](2,3-difluoro-6- methoxyphenyl)methanone (R547), A Potent and Selective Cyclin-Dependent Kinase Inhibitor with Significant in Vivo Antitumor Activity

  摘要：

  The cyclin-dependent kinases (CDKs) and their cyclin partners are key regulators of the cell cycle. Since deregulation of CDKs is found with high frequency in many human cancer cells, pharmacological inhibition of CDKs with small molecules has the potential to provide an effective strategy for the treatment of cancer. The 2,4-diamino-5-ketopyrimidines 6 reported here represent a novel class of potent and ATP-competitive inhibitors that selectively target the cyclin-dependent kinase family. This diaminopyrimidine core with a substituted 4-piperidine moiety on the C2-amino position and 2-methoxybenzoyl at the C5 position has been identified as the critical structure responsible for the CDK inhibitory activity. Further optimization has led to a good number of analogues that show potent inhibitory activities against CDK1, CDK2, and CDK4 but are inactive against a large panel of serine/threonine and tyrosine kinases (K-i > 10 AM). As one of these representative analogues, compound 39 (R547) has the best CDK inhibitory activities (K-i = 0.001, 0.003, and 0.001 AM for CDK1, CDK2, and CDK4, respectively) and excellent in vitro cellular potency, inhibiting the growth of various human tumor cell lines including an HCT116 cell line (IC50 = 0.08 mu M). An X-ray crystal structure of 39 bound to CDK2 has been determined in this study, revealing a binding mode that is consistent with our SAR. Compound 39 demonstrates significant in vivo efficacy in the HCT116 human colorectal tumor xenograft model in nude mice with up to 95% tumor growth inhibition. On the basis of its superior overall profile, 39 was chosen for further evaluation and has progressed into Phase I clinical trial for the treatment of cancer.

  DOI：

  10.1021/jm0606138
• 作为产物：
  描述：

  2-乙基巯基-4-氨基嘧啶-5-羧酸 在 正丁基锂 、 1-羟基苯并三唑 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 正己烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.92h， 生成 (4-amino-2-ethylsulfanylpyrimidin-5-yl)(4-fluoro-2-methoxyphenyl)methanone
  参考文献：
  名称：

  Discovery of [4-Amino-2-(1-methanesulfonylpiperidin-4-ylamino)pyrimidin-5-yl](2,3-difluoro-6- methoxyphenyl)methanone (R547), A Potent and Selective Cyclin-Dependent Kinase Inhibitor with Significant in Vivo Antitumor Activity

  摘要：

  The cyclin-dependent kinases (CDKs) and their cyclin partners are key regulators of the cell cycle. Since deregulation of CDKs is found with high frequency in many human cancer cells, pharmacological inhibition of CDKs with small molecules has the potential to provide an effective strategy for the treatment of cancer. The 2,4-diamino-5-ketopyrimidines 6 reported here represent a novel class of potent and ATP-competitive inhibitors that selectively target the cyclin-dependent kinase family. This diaminopyrimidine core with a substituted 4-piperidine moiety on the C2-amino position and 2-methoxybenzoyl at the C5 position has been identified as the critical structure responsible for the CDK inhibitory activity. Further optimization has led to a good number of analogues that show potent inhibitory activities against CDK1, CDK2, and CDK4 but are inactive against a large panel of serine/threonine and tyrosine kinases (K-i > 10 AM). As one of these representative analogues, compound 39 (R547) has the best CDK inhibitory activities (K-i = 0.001, 0.003, and 0.001 AM for CDK1, CDK2, and CDK4, respectively) and excellent in vitro cellular potency, inhibiting the growth of various human tumor cell lines including an HCT116 cell line (IC50 = 0.08 mu M). An X-ray crystal structure of 39 bound to CDK2 has been determined in this study, revealing a binding mode that is consistent with our SAR. Compound 39 demonstrates significant in vivo efficacy in the HCT116 human colorectal tumor xenograft model in nude mice with up to 95% tumor growth inhibition. On the basis of its superior overall profile, 39 was chosen for further evaluation and has progressed into Phase I clinical trial for the treatment of cancer.

  DOI：

  10.1021/jm0606138

文献信息

• US7615634B2
  申请人：——

  公开号：US7615634B2

  公开（公告）日：2009-11-10
• Discovery of [4-Amino-2-(1-methanesulfonylpiperidin-4-ylamino)pyrimidin-5-yl](2,3-difluoro-6- methoxyphenyl)methanone (R547), A Potent and Selective Cyclin-Dependent Kinase Inhibitor with Significant in Vivo Antitumor Activity
  作者：Xin-Jie Chu、Wanda DePinto、David Bartkovitz、Sung-Sau So、Binh T. Vu、Kathryn Packman、Christine Lukacs、Qingjie Ding、Nan Jiang、Ka Wang、Petra Goelzer、Xuefeng Yin、Melissa A. Smith、Brian X. Higgins、Yingsi Chen、Qing Xiang、John Moliterni、Gerald Kaplan、Bradford Graves、Allen Lovey、Nader Fotouhi

  DOI：10.1021/jm0606138

  日期：2006.11.1

  The cyclin-dependent kinases (CDKs) and their cyclin partners are key regulators of the cell cycle. Since deregulation of CDKs is found with high frequency in many human cancer cells, pharmacological inhibition of CDKs with small molecules has the potential to provide an effective strategy for the treatment of cancer. The 2,4-diamino-5-ketopyrimidines 6 reported here represent a novel class of potent and ATP-competitive inhibitors that selectively target the cyclin-dependent kinase family. This diaminopyrimidine core with a substituted 4-piperidine moiety on the C2-amino position and 2-methoxybenzoyl at the C5 position has been identified as the critical structure responsible for the CDK inhibitory activity. Further optimization has led to a good number of analogues that show potent inhibitory activities against CDK1, CDK2, and CDK4 but are inactive against a large panel of serine/threonine and tyrosine kinases (K-i > 10 AM). As one of these representative analogues, compound 39 (R547) has the best CDK inhibitory activities (K-i = 0.001, 0.003, and 0.001 AM for CDK1, CDK2, and CDK4, respectively) and excellent in vitro cellular potency, inhibiting the growth of various human tumor cell lines including an HCT116 cell line (IC50 = 0.08 mu M). An X-ray crystal structure of 39 bound to CDK2 has been determined in this study, revealing a binding mode that is consistent with our SAR. Compound 39 demonstrates significant in vivo efficacy in the HCT116 human colorectal tumor xenograft model in nude mice with up to 95% tumor growth inhibition. On the basis of its superior overall profile, 39 was chosen for further evaluation and has progressed into Phase I clinical trial for the treatment of cancer.