(R)-2-((7-(benzylamino)-3-iso-propylpyrazolo[1,5-a]pyrimidin-5-yl)amino)-8-(pyridin-2-yl)octan-1-ol | 1092443-72-5

• 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)-2-((7-(benzylamino)-3-iso-propylpyrazolo[1,5-a]pyrimidin-5-yl)amino)-8-(pyridin-2-yl)octan-1-ol
• 英文别名: (2R)-2-[[7-(benzylamino)-3-propan-2-ylpyrazolo[1,5-a]pyrimidin-5-yl]amino]-8-pyridin-2-yloctan-1-ol
• CAS: 1092443-72-5
• 化学式: C₂₉H₃₈N₆O
• 分子量: 486.66
• InChiKey: ZSBLMEWEEOQXEJ-RUZDIDTESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6
• 重原子数：
  36
• 可旋转键数：
  14
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  87.4
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  (R)-tert-butyl benzyl(5-((1-hydroxy-8-(pyridin-2-yl)octan-2-yl)amino)-3-isopropylpyrazolo[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61%的产率得到(R)-2-((7-(benzylamino)-3-iso-propylpyrazolo[1,5-a]pyrimidin-5-yl)amino)-8-(pyridin-2-yl)octan-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

文献信息

• Selective Inhibitors for Cyclin-Dependent Kinases
  申请人：Jogalekar Ashutosh S.

  公开号：US20100261683A1

  公开（公告）日：2010-10-14

  This invention provides a class of compounds which are useful for specifically inhibiting cyclin-dependent kinases. This class of compounds finds use in treating diseases resulting from inappropriate activity of cyclin-dependent kinases, including cancer, viral infections (e.g., HIV) neurodegenerative disorders (e.g. Alzheimer's disease), and cardiovascular disorders (e.g. atherosclerosis). Moreover, certain members of this class are particularly useful for inhibiting cyclin-dependent kinase 7 and are especially useful for the treatment of breast cancer.

  本发明提供了一类化合物，可用于特异性抑制细胞周期依赖性激酶。这类化合物可用于治疗由于细胞周期依赖性激酶不适当活动引起的疾病，包括癌症、病毒感染（例如HIV）、神经退行性疾病（例如阿尔茨海默病）和心血管疾病（例如动脉硬化）。此外，该类化合物的某些成员特别适用于抑制细胞周期依赖性激酶7，并且特别适用于治疗乳腺癌。
• US8067424B2
  申请人：——

  公开号：US8067424B2

  公开（公告）日：2011-11-29
• A Novel Pyrazolo[1,5-<i>a</i>]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
  作者：Dean A. Heathcote、Hetal Patel、Sebastian H. B. Kroll、Pascale Hazel、Manikandan Periyasamy、Mary Alikian、Seshu K. Kanneganti、Ashutosh S. Jogalekar、Bodo Scheiper、Marion Barbazanges、Andreas Blum、Jan Brackow、Alekasandra Siwicka、Robert D. M. Pace、Matthew J. Fuchter、James P. Snyder、Dennis C. Liotta、Paul. S. Freemont、Eric O. Aboagye、R. Charles Coombes、Anthony G. M. Barrett、Simak Ali

  DOI：10.1021/jm100732t

  日期：2010.12.23

  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.