(2S)-2-[(2S)-4-[5-fluoro-6-(2H-pyrazolo[3,4-b]pyridin-3-yl)pyridin-2-yl]piperazin-2-yl]-3-methylbutan-2-ol | 1422207-14-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: (2S)-2-[(2S)-4-[5-fluoro-6-(2H-pyrazolo[3,4-b]pyridin-3-yl)pyridin-2-yl]piperazin-2-yl]-3-methylbutan-2-ol
• CAS: 1422207-14-4
• 化学式: C₂₀H₂₅FN₆O
• 分子量: 384.457
• InChiKey: PDSONWYECZHBAE-YWZLYKJASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  90
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  2-氟-N-甲氧基-N-甲基烟酰胺 在 三乙烯二胺 、 正丁基锂 、 一水合肼 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 N-甲基吡咯烷酮 、 正己烷 、 甲基叔丁基醚 为溶剂， 反应 3.0h， 生成 (2R)-2-[(2S)-4-[5-fluoro-6-(2H-pyrazolo[3,4-b]pyridin-3-yl)pyridin-2-yl]piperazin-2-yl]-3-methylbutan-2-ol 、 (2S)-2-[(2R)-4-[5-fluoro-6-(2H-pyrazolo[3,4-b]pyridin-3-yl)pyridin-2-yl]piperazin-2-yl]-3-methylbutan-2-ol 、 (2S)-2-[(2S)-4-[5-fluoro-6-(2H-pyrazolo[3,4-b]pyridin-3-yl)pyridin-2-yl]piperazin-2-yl]-3-methylbutan-2-ol 、 (2R)-2-[(2R)-4-[5-fluoro-6-(2H-pyrazolo[3,4-b]pyridin-3-yl)pyridin-2-yl]piperazin-2-yl]-3-methylbutan-2-ol
  参考文献：
  名称：

  Design and Optimization of Selective Protein Kinase C θ (PKCθ) Inhibitors for the Treatment of Autoimmune Diseases

  摘要：

  Protein kinase C theta (PKC theta) has a central role in T cell activation and survival; however, the dependency of T cell responses to the inhibition of this enzyme appears to be dictated by the nature of the antigen and by the inflammatory environment. Studies in PKC theta-deficient mice have demonstrated that while antiviral responses are PKC theta-independent, T cell responses associated with autoimmune diseases are PKC theta-dependent. Thus, potent and selective inhibition of PKC theta is expected to block autoimmune T cell responses without compromising antiviral immunity. Herein, we describe the development of potent and selective PKC theta inhibitors, which show exceptional potency in cells and in vivo. By use of a structure based rational design approach, a 1000-fold improvement in potency and 76-fold improvement in selectivity over closely related PKC isoforms such as PKC delta were obtained from the initial HTS hit, together with a big improvement in lipophilic efficiency (LiPE).

  DOI：

  10.1021/jm301465a

文献信息

• Design and Optimization of Selective Protein Kinase C θ (PKCθ) Inhibitors for the Treatment of Autoimmune Diseases
  作者：Juan-Miguel Jimenez、Dean Boyall、Guy Brenchley、Philip N. Collier、Christopher J. Davis、Damien Fraysse、Shazia B. Keily、Jaclyn Henderson、Andrew Miller、Francoise Pierard、Luca Settimo、Heather C. Twin、Claire M. Bolton、Adam P. Curnock、Peter Chiu、Adam J. Tanner、Stephen Young

  DOI：10.1021/jm301465a

  日期：2013.3.14

  Protein kinase C theta (PKC theta) has a central role in T cell activation and survival; however, the dependency of T cell responses to the inhibition of this enzyme appears to be dictated by the nature of the antigen and by the inflammatory environment. Studies in PKC theta-deficient mice have demonstrated that while antiviral responses are PKC theta-independent, T cell responses associated with autoimmune diseases are PKC theta-dependent. Thus, potent and selective inhibition of PKC theta is expected to block autoimmune T cell responses without compromising antiviral immunity. Herein, we describe the development of potent and selective PKC theta inhibitors, which show exceptional potency in cells and in vivo. By use of a structure based rational design approach, a 1000-fold improvement in potency and 76-fold improvement in selectivity over closely related PKC isoforms such as PKC delta were obtained from the initial HTS hit, together with a big improvement in lipophilic efficiency (LiPE).