3-(5-cyclopropylisoxazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

• 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: 3-(5-cyclopropylisoxazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
• 英文别名: 3-(5-cyclopropyl-1,2-oxazol-3-yl)-2H-pyrazolo[3,4-d]pyrimidin-4-amine
• 化学式: C₁₁H₁₀N₆O
• 分子量: 242.24
• InChiKey: RXSPIELJIFZXML-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  107
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  甲基环氧丙烷 、 3-(5-cyclopropylisoxazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 在 caesium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 以32%的产率得到1-(4-amino-3-(5-cyclopropylisoxazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-methylpropan-2-ol
  参考文献：
  名称：

  A Pyrazolo[3,4-d]pyrimidin-4-amine Derivative Containing an Isoxazole Moiety Is a Selective and Potent Inhibitor of RET Gatekeeper Mutants

  摘要：

  Aberrant RET kinase signaling plays critical roles in several human cancers such as thyroid carcinoma. The gatekeeper mutants (V804L or V804M) of RET are resistant to currently approved RET inhibitors such as cabozantinib and vandetanib. We, for the first time, report a highly selective and extremely potent RET inhibitor, 6i rationally designed. Compound 6i inhibits strongly RET gatekeeper mutants and other clinically relevant RET mutants as well as wt-RET. This substance also significantly suppresses growth of thyroid cancer-derived TT cell lines and Ba/F3 cells transformed with various RET mutants. Docking studies reveal that the isoxazole moiety in 6i is responsible for binding affinity improvement by providing additional site for H-bonding with Lys758. Also, 6i not only substantially blocks cellular RET autophosphorylation and its downstream pathway, it markedly induces apoptosis and anchorage-independent growth inhibition in TT cell lines while having no effect on normal thyroid Nthy ori-3-1 cells.

  DOI：

  10.1021/acs.jmedchem.5b01522
• 作为产物：
  描述：

  5-环丙基异噁唑-3-甲酸乙酯 在 草酰氯 、 盐酸羟胺 、 三乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 28.5h， 生成 3-(5-cyclopropylisoxazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
  参考文献：
  名称：

  A Pyrazolo[3,4-d]pyrimidin-4-amine Derivative Containing an Isoxazole Moiety Is a Selective and Potent Inhibitor of RET Gatekeeper Mutants

  摘要：

  Aberrant RET kinase signaling plays critical roles in several human cancers such as thyroid carcinoma. The gatekeeper mutants (V804L or V804M) of RET are resistant to currently approved RET inhibitors such as cabozantinib and vandetanib. We, for the first time, report a highly selective and extremely potent RET inhibitor, 6i rationally designed. Compound 6i inhibits strongly RET gatekeeper mutants and other clinically relevant RET mutants as well as wt-RET. This substance also significantly suppresses growth of thyroid cancer-derived TT cell lines and Ba/F3 cells transformed with various RET mutants. Docking studies reveal that the isoxazole moiety in 6i is responsible for binding affinity improvement by providing additional site for H-bonding with Lys758. Also, 6i not only substantially blocks cellular RET autophosphorylation and its downstream pathway, it markedly induces apoptosis and anchorage-independent growth inhibition in TT cell lines while having no effect on normal thyroid Nthy ori-3-1 cells.

  DOI：

  10.1021/acs.jmedchem.5b01522

文献信息

• [EN] NOVEL 3-(ISOXAZOL-3-YL)-PYRAZOLO[3,4-D]PYRIMIDIN-4-AMINE COMPOUND, WHICH IS RET KINASE INHIBITOR<br/>[FR] NOUVEAU COMPOSÉ 3-(ISOXAZOL-3-YL)-PYRAZOLO[3,4-D]PYRIMIDIN-4-AMINE, QUI EST UN INHIBITEUR DE LA KINASE RET<br/>[KO] RET 키나아제 저해제인 신규 3-(이속사졸-3-일)-피라졸로[3,4-디]피리미딘-4-아민 화합물
  申请人：KOREA INST SCI & TECH

  公开号：WO2017026718A1

  公开（公告）日：2017-02-16

  본 발명은 신규 3-(이속사졸-3-일)-피라졸로[3,4-d]피리미딘-4-아민 화합물, 이 화합물 제조방법, 그리고 이 화합물의 RET 키나아제 활성으로 야기되는 각종 암질환의 예방 및 치료에 사용하는 의약용도에 관한 것이다.
• A Pyrazolo[3,4-<i>d</i>]pyrimidin-4-amine Derivative Containing an Isoxazole Moiety Is a Selective and Potent Inhibitor of RET Gatekeeper Mutants
  作者：Hojong Yoon、Yeonui Kwak、Seunghye Choi、Hanna Cho、Nam Doo Kim、Taebo Sim

  DOI：10.1021/acs.jmedchem.5b01522

  日期：2016.1.14

  Aberrant RET kinase signaling plays critical roles in several human cancers such as thyroid carcinoma. The gatekeeper mutants (V804L or V804M) of RET are resistant to currently approved RET inhibitors such as cabozantinib and vandetanib. We, for the first time, report a highly selective and extremely potent RET inhibitor, 6i rationally designed. Compound 6i inhibits strongly RET gatekeeper mutants and other clinically relevant RET mutants as well as wt-RET. This substance also significantly suppresses growth of thyroid cancer-derived TT cell lines and Ba/F3 cells transformed with various RET mutants. Docking studies reveal that the isoxazole moiety in 6i is responsible for binding affinity improvement by providing additional site for H-bonding with Lys758. Also, 6i not only substantially blocks cellular RET autophosphorylation and its downstream pathway, it markedly induces apoptosis and anchorage-independent growth inhibition in TT cell lines while having no effect on normal thyroid Nthy ori-3-1 cells.