tert-butyl-(R)-3-(4-amino-3-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: tert-butyl-(R)-3-(4-amino-3-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate
• 英文别名: tert-butyl (3R)-3-[4-amino-3-[3-(trifluoromethyl)phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate
• 化学式: C₂₂H₂₅F₃N₆O₂
• 分子量: 462.475
• InChiKey: BQEKTJBNFUSANH-OAHLLOKOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  33
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  99.2
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  tert-butyl-(R)-3-(4-amino-3-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate 在 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 1.25h， 生成 (R)-1-(3-(4-amino-3-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one
  参考文献：
  名称：

  Structure-Guided Development of Covalent and Mutant-Selective Pyrazolopyrimidines to Target T790M Drug Resistance in Epidermal Growth Factor Receptor

  摘要：

  Reversible epidermal growth factor receptor (BUR) inhibitors prompt a beneficial clinical response in non-small cell lung cancer patients-who harbor activating mutations in EGFR. However, resistance mutations, particularly the gatekeeper mutation T790M, limit this efficacy. Here, we describe a structure-guided development of a series of covalent and mutant-selective EGFR inhibitors that effectively target the T790M mutant. The pyrazolopyrimidine-based core differs structurally from that of aminopyrimidine-based third-generation EGFR inhibitors and therefore constitutes a new set of inhibitors that target this mechanism of drug resistance. These inhibitors exhibited strong inhibitory effects toward EGFR kinase activity and excellent inhibition of cell growth in the drug resistant cell line H1975, without significantly affecting EGFR wild-type cell lines. Additionally, we present the in vitro ADME/DMPR parameters for a subset of the inhibitors as well as in vivo pharmacokinetics in mice for a candidate with promising activity profile.

  DOI：

  10.1021/acs.jmedchem.7b00515
• 作为产物：
  描述：

  (S)-1-叔丁氧羰基-3-羟基哌啶 在 palladium bis[bis(diphenylphosphino)ferrocene] dichloride 、 偶氮二甲酸二异丙酯 、 potassium carbonate 、 三苯基膦 作用下， 以 四氢呋喃 、 1,4-二氧六环 为溶剂， 反应 32.0h， 生成 tert-butyl-(R)-3-(4-amino-3-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate
  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

• 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.
• Structure-Guided Development of Covalent and Mutant-Selective Pyrazolopyrimidines to Target T790M Drug Resistance in Epidermal Growth Factor Receptor
  作者：Julian Engel、Steven Smith、Jonas Lategahn、Hannah L. Tumbrink、Lisa Goebel、Christian Becker、Elisabeth Hennes、Marina Keul、Anke Unger、Heiko Müller、Matthias Baumann、Carsten Schultz-Fademrecht、Georgia Günther、Jan G. Hengstler、Daniel Rauh

  DOI：10.1021/acs.jmedchem.7b00515

  日期：2017.9.28

  Reversible epidermal growth factor receptor (BUR) inhibitors prompt a beneficial clinical response in non-small cell lung cancer patients-who harbor activating mutations in EGFR. However, resistance mutations, particularly the gatekeeper mutation T790M, limit this efficacy. Here, we describe a structure-guided development of a series of covalent and mutant-selective EGFR inhibitors that effectively target the T790M mutant. The pyrazolopyrimidine-based core differs structurally from that of aminopyrimidine-based third-generation EGFR inhibitors and therefore constitutes a new set of inhibitors that target this mechanism of drug resistance. These inhibitors exhibited strong inhibitory effects toward EGFR kinase activity and excellent inhibition of cell growth in the drug resistant cell line H1975, without significantly affecting EGFR wild-type cell lines. Additionally, we present the in vitro ADME/DMPR parameters for a subset of the inhibitors as well as in vivo pharmacokinetics in mice for a candidate with promising activity profile.