(R)-1-(3-(4-amino-3-(3-fluorophenyl)-1H-pyrazolo[3,4-d]-pyrimidin-1-yl)piperidin-1-yl)propan-1-one

• 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)-1-(3-(4-amino-3-(3-fluorophenyl)-1H-pyrazolo[3,4-d]-pyrimidin-1-yl)piperidin-1-yl)propan-1-one
• 英文别名: 1-[(3R)-3-[4-amino-3-(3-fluorophenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]propan-1-one
• 化学式: C₁₉H₂₁FN₆O
• 分子量: 368.414
• InChiKey: BCVDNVLVZIDDSO-CQSZACIVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  27
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  89.9
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  (R)-3-(4-氨基-3-碘-1H-吡唑并[3,4-D]嘧啶-1-基)哌啶-1-羧酸叔丁酯 在 sodium carbonate 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 乙二醇二甲醚 、 乙醇 、 二氯甲烷 为溶剂， 反应 13.33h， 生成 (R)-1-(3-(4-amino-3-(3-fluorophenyl)-1H-pyrazolo[3,4-d]-pyrimidin-1-yl)piperidin-1-yl)propan-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

文献信息

• 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.