[({[(2R,3S,4R,5R)-5-(6-chloro-4-[[(1S)-1-(4-fluorophenyl)ethyl]amino]-1H-pyrazolo[3,4-b]pyridin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy}(hydroxy)phosphoryl)methyl]phosphonic acid

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: [({[(2R,3S,4R,5R)-5-(6-chloro-4-[[(1S)-1-(4-fluorophenyl)ethyl]amino]-1H-pyrazolo[3,4-b]pyridin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy}(hydroxy)phosphoryl)methyl]phosphonic acid
• 英文别名: [[(2~{R},3~{S},4~{R},5~{R})-5-[6-chloranyl-4-[[(1~{S})-1-(4-fluorophenyl)ethyl]amino]pyrazolo[3,4-b]pyridin-1-yl]-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl]methylphosphonic acid；[[(2R,3S,4R,5R)-5-[6-chloro-4-[[(1S)-1-(4-fluorophenyl)ethyl]amino]pyrazolo[3,4-b]pyridin-1-yl]-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]methylphosphonic acid
• 化学式: C₂₀H₂₄ClFN₄O₉P₂
• 分子量: 580.831
• InChiKey: ZOJVDXWVVGFWSE-KCVUFLITSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.7
• 重原子数：
  37
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  197
• 氢给体数：
  6
• 氢受体数：
  13

反应信息

• 作为产物：
  描述：

  在 氨 作用下， 以 甲醇 为溶剂， 反应 29.25h， 生成 [({[(2R,3S,4R,5R)-5-(6-chloro-4-[[(1S)-1-(4-fluorophenyl)ethyl]amino]-1H-pyrazolo[3,4-b]pyridin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy}(hydroxy)phosphoryl)methyl]phosphonic acid
  参考文献：
  名称：

  AB680的发现：一种有效的CD73选择性抑制剂。

  摘要：

  高浓度存在于肿瘤微环境（TME）中的细胞外腺苷（ADO）通过抑制T细胞和NK细胞活化来抑制免疫功能。ADO的瘤内生成取决于两个胞外核苷酸酶CD39（ATP→AMP）和CD73（AMP→ADO）对ATP的顺序分解代谢。抑制CD73消除了TME中ADO产生的主要途径，并且可以逆转ADO介导的免疫抑制。广泛的结构-活性关系（SAR）询问，基于结构的药物设计以及药代动力学特性的优化最终导致了AB680的发现，AB680是一种非常有效的（K i= 5 pM），可逆的CD73选择性抑制剂。AB680的特征还在于其临床前物种的清除率极低且半衰期较长，从而导致适合长效肠胃外给药的PK曲线。目前正在1期临床试验中评估AB680。初始数据显示AB680具有良好的耐受性，并具有适合于每两周一次（Q2W）静脉内静脉给药的药代动力学特征。

  DOI：

  10.1021/acs.jmedchem.0c00525

文献信息

• Modulators of 5′-nucleotidase, ecto and the use thereof
  申请人：ARCUS BIOSCIENCES, INC.

  公开号：US10239912B2

  公开（公告）日：2019-03-26

  Compounds that modulate the conversion of AMP to adenosine by 5′-nucleotidase, ecto, and compositions containing the compounds and methods for synthesizing the compounds, are described herein. The use of such compounds and compositions for the treatment and/or prevention of a diverse array of diseases, disorders and conditions, including cancer- and immune-related disorders, that are mediated by 5′-nucleotidase, ecto is also provided.

  本文描述了调节 5′-核苷酸酶将 AMP 转化为腺苷的化合物，以及含有这些化合物的组合物和合成这些化合物的方法。还提供了这些化合物和组合物用于治疗和/或预防由 5′-核苷酸酶外切酶介导的各种疾病、失调和病症，包括癌症和免疫相关失调。
• MODULATORS OF 5'-NUCLEOTIDASE, ECTO AND THE USE THEREOF
  申请人：ARCUS BIOSCIENCES, INC.

  公开号：US20170267710A1

  公开（公告）日：2017-09-21

  Compounds that modulate the conversion of AMP to adenosine by 5′-nucleotidase, ecto, and compositions containing the compounds and methods for synthesizing the compounds, are described herein. The use of such compounds and compositions for the treatment and/or prevention of a diverse array of diseases, disorders and conditions, including cancer- and immune-related disorders, that are mediated by 5′-nucleotidase, ecto is also provided.
• PARENTERALLY ADMINISTERED IMMUNE ENHANCING DRUGS
  申请人：ARCUS BIOSCIENCES, INC.

  公开号：US20200405629A1

  公开（公告）日：2020-12-31

  Methods of identifying compounds that modulate the conversion of AMP to adenosine by 5′-nucleotidase, ecto, and that possess particular pharmacokinetic characteristics are described herein. Methods of such compounds, and compositions comprising same, for the treatment and/or prevention of a diverse array of diseases, disorders and conditions, including cancer- and immune-related disorders, are also provided.
• [EN] PARENTERALLY ADMINISTERED IMMUNE ENHANCING DRUGS<br/>[FR] MÉDICAMENTS RENFORÇANT L'IMMUNITÉ ADMINISTRÉS PAR VOIE PARENTÉRALE
  申请人：ARCUS BIOSCIENCES INC

  公开号：WO2019173682A1

  公开（公告）日：2019-09-12

  Methods of identifying compounds that modulate the conversion of AMP to adenosine by 5'-nucleotidase, ecto, and that possess particular pharmacokinetic characteristics are described herein. Methods of such compounds, and compositions comprising same, for the treatment and/or prevention of a diverse array of diseases, disorders and conditions, including cancer- and immune-related disorders, are also provided.