(R)-tert-butyl benzyl(5-((2,2,3,3,15,15-hexamethyl-13-oxo-4,14-dioxa-12-aza-3-silahexadecan-6-yl)amino)-3-iso-propylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate | 1256288-46-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡唑并嘧啶类
• 英文名称: (R)-tert-butyl benzyl(5-((2,2,3,3,15,15-hexamethyl-13-oxo-4,14-dioxa-12-aza-3-silahexadecan-6-yl)amino)-3-iso-propylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate
• CAS: 1256288-46-6
• 化学式: C₃₉H₆₄N₆O₅Si
• 分子量: 725.06
• InChiKey: YEAUYASPPUBPKC-SSEXGKCCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  9.68
• 重原子数：
  51.0
• 可旋转键数：
  15.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  119.32
• 氢给体数：
  2.0
• 氢受体数：
  9.0

反应信息

• 作为反应物：
  描述：

  (R)-tert-butyl benzyl(5-((2,2,3,3,15,15-hexamethyl-13-oxo-4,14-dioxa-12-aza-3-silahexadecan-6-yl)amino)-3-iso-propylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate 在 盐酸 作用下， 以 甲醇 、 水 为溶剂， 反应 3.0h， 以59%的产率得到(R)-7-amino-2-((7-(benzylamino)-3-iso-propylpyrazolo[1,5-a]pyrimidin-5-yl)amino)heptan-1-ol
  参考文献：
  名称：

  A Novel Pyrazolo[1,5-a]pyrimidine Is a Potent Inhibitor of Cyclin-Dependent Protein Kinases 1, 2, and 9, Which Demonstrates Antitumor Effects in Human Tumor Xenografts Following Oral Administration

  摘要：

  Cyclin-dependent protein kinases (CDKs) are central to the appropriate regulation of cell proliferation, apoptosis, and gene expression. Abnormalities in CDK activity and regulation are common features of cancer, making CDK family members attractive targets for the development of anticancer drugs. Here, we report the identification of a pyrazolo[1,5-a]pyrimidine derived compound, 4k (BS-194), as a selective and potent CDK inhibitor, which inhibits CDK2, CDK1, CDK5, CDK7, and CDK9 (IC50 = 3, 30, 30, 250, and 90 nmol/L, respectively). Cell-based studies showed inhibition of the phosphorylation of CDK substrates, Rb and the RNA polymerase II C-terminal domain, down-regulation of cyclins A, E, and D1, and cell cycle block in the S and G(2)/M phases. Consistent with these findings, 4k demonstrated potent antiproliferative activity in 60 cancer cell lines tested (mean GI(50) = 280 nmol/L). Pharmacokinetic studies showed that 4k is orally bioavailable, with an elimination half-life of 178 min following oral dosing in mice. When administered at a concentration of 25 mg/kg orally, 4k inhibited human tumor xenografts and suppressed CDK substrate phosphorylation. These findings identify 4k as a novel, potent CDK selective inhibitor with potential for oral delivery in cancer patients.

  DOI：

  10.1021/jm100732t
• 作为产物：
  描述：

  tert-butyl benzyi(S-chloro-3-iso-propyl pyrazolo[1,5-a]pyrimidin-7-yl)carbamate 、 (R)-tert-butyl (6-amino-7-((tert-butyldimethylsilyl)oxy)heptyl)carbamate 在 tris-(dibenzylideneacetone)dipalladium(0) 、 BINAP 、 sodium t-butanolate 作用下， 以 甲苯 为溶剂， 反应 16.25h， 以32%的产率得到(R)-tert-butyl benzyl(5-((2,2,3,3,15,15-hexamethyl-13-oxo-4,14-dioxa-12-aza-3-silahexadecan-6-yl)amino)-3-iso-propylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate
  参考文献：
  名称：

  A Novel Pyrazolo[1,5-a]pyrimidine Is a Potent Inhibitor of Cyclin-Dependent Protein Kinases 1, 2, and 9, Which Demonstrates Antitumor Effects in Human Tumor Xenografts Following Oral Administration

  摘要：

  Cyclin-dependent protein kinases (CDKs) are central to the appropriate regulation of cell proliferation, apoptosis, and gene expression. Abnormalities in CDK activity and regulation are common features of cancer, making CDK family members attractive targets for the development of anticancer drugs. Here, we report the identification of a pyrazolo[1,5-a]pyrimidine derived compound, 4k (BS-194), as a selective and potent CDK inhibitor, which inhibits CDK2, CDK1, CDK5, CDK7, and CDK9 (IC50 = 3, 30, 30, 250, and 90 nmol/L, respectively). Cell-based studies showed inhibition of the phosphorylation of CDK substrates, Rb and the RNA polymerase II C-terminal domain, down-regulation of cyclins A, E, and D1, and cell cycle block in the S and G(2)/M phases. Consistent with these findings, 4k demonstrated potent antiproliferative activity in 60 cancer cell lines tested (mean GI(50) = 280 nmol/L). Pharmacokinetic studies showed that 4k is orally bioavailable, with an elimination half-life of 178 min following oral dosing in mice. When administered at a concentration of 25 mg/kg orally, 4k inhibited human tumor xenografts and suppressed CDK substrate phosphorylation. These findings identify 4k as a novel, potent CDK selective inhibitor with potential for oral delivery in cancer patients.

  DOI：

  10.1021/jm100732t