1-[(3R)-3-[4-amino-3-(4-methoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one | 1407966-47-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 1-[(3R)-3-[4-amino-3-(4-methoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one
• CAS: 1407966-47-5
• 化学式: C₂₀H₂₂N₆O₂
• 分子量: 378.434
• InChiKey: KFTSORBGYVVIBF-CQSZACIVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  99.2
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  (S)-1-叔丁氧羰基-3-羟基哌啶 在 盐酸 、 偶氮二甲酸二异丙酯 、 potassium carbonate 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 三苯基膦 作用下， 以 四氢呋喃 、 1,4-二氧六环 为溶剂， 反应 28.25h， 生成 1-[(3R)-3-[4-amino-3-(4-methoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one
  参考文献：
  名称：

  Covalent Inhibitors of Interleukin-2 Inducible T Cell Kinase (Itk) with Nanomolar Potency in a Whole-Blood Assay

  摘要：

  We wish to report a strategy that targets interleukin-2 inducible T cell kinase (Itk) with covalent inhibitors. Thus far, covalent inhibition of Itk has not been disclosed in the literature. Structure-based drug design was utilized to achieve low nanomolar potency of the disclosed series even at high ATP concentrations. Kinetic measurements confirmed an irreversible binding mode with off-rate half-lives exceeding 24 h and moderate on-rates. The analogues are highly potent in a cellular IP1 assay as well as in a human whole-blood (hWB) assay. Despite a half-life of approximately 2 h in resting primary T cells, the covalent inhibition of Itk resulted in functional silencing of the TCR pathway for more than 24 h. This prolonged effect indicates that covalent inhibition is a viable strategy to target the inactivation of Itk.

  DOI：

  10.1021/jm301190s

文献信息

• PYRAZOLO[3,4-d]PYRIMIDINE AND PYRROLO[2,3-d]PYRIMIDINE COMPOUNDS AS KINASE INHIBITORS
  申请人：CHEN Wei

  公开号：US20130172314A1

  公开（公告）日：2013-07-04

  Disclosed herein are compounds that form covalent bonds with Bruton's tyrosine kinase (Btk). Also described are irreversible inhibitors of Btk. Methods for the preparation of the compounds are disclosed. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the Btk inhibitors are disclosed, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions.

  本文披露了一些与布鲁顿酪氨酸激酶（Btk）形成共价键的化合物。还描述了Btk的不可逆抑制剂。披露了制备这些化合物的方法。还披露了包括这些化合物的制药组合物。披露了使用Btk抑制剂的方法，单独或与其他治疗剂一起治疗自身免疫性疾病或病况、异种免疫性疾病或病况、癌症（包括淋巴瘤）和炎症性疾病或病况。
• US8377946B1
  申请人：——

  公开号：US8377946B1

  公开（公告）日：2013-02-19
• US9273051B2
  申请人：——

  公开号：US9273051B2

  公开（公告）日：2016-03-01
• US9546172B2
  申请人：——

  公开号：US9546172B2

  公开（公告）日：2017-01-17
• Covalent Inhibitors of Interleukin-2 Inducible T Cell Kinase (Itk) with Nanomolar Potency in a Whole-Blood Assay
  作者：Christoph W. Zapf、Brian S. Gerstenberger、Li Xing、David C. Limburg、David R. Anderson、Nicole Caspers、Seungil Han、Ann Aulabaugh、Ravi Kurumbail、Subarna Shakya、Xin Li、Vikki Spaulding、Robert M. Czerwinski、Nilufer Seth、Quintus G. Medley

  DOI：10.1021/jm301190s

  日期：2012.11.26

  We wish to report a strategy that targets interleukin-2 inducible T cell kinase (Itk) with covalent inhibitors. Thus far, covalent inhibition of Itk has not been disclosed in the literature. Structure-based drug design was utilized to achieve low nanomolar potency of the disclosed series even at high ATP concentrations. Kinetic measurements confirmed an irreversible binding mode with off-rate half-lives exceeding 24 h and moderate on-rates. The analogues are highly potent in a cellular IP1 assay as well as in a human whole-blood (hWB) assay. Despite a half-life of approximately 2 h in resting primary T cells, the covalent inhibition of Itk resulted in functional silencing of the TCR pathway for more than 24 h. This prolonged effect indicates that covalent inhibition is a viable strategy to target the inactivation of Itk.