N²-((1H-indol-5-yl)methyl)-N⁴-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine | 1425928-98-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: N²-((1H-indol-5-yl)methyl)-N⁴-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine
• 英文别名: 4-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-N-(1H-indol-5-ylmethyl)pyrimidine-2,4-diamine
• CAS: 1425928-98-8
• 化学式: C₁₉H₁₉N₇
• 分子量: 345.407
• InChiKey: MERRGQWRCCBKDB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  26
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  94.3
• 氢给体数：
  4
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  3-氨基-5-环丙基-1H-吡唑 在 N,N-二异丙基乙胺 作用下， 以 乙醇 、 二甲基亚砜 为溶剂， 反应 18.0h， 生成 N²-((1H-indol-5-yl)methyl)-N⁴-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine
  参考文献：
  名称：

  Structure-Guided Design of Group I Selective p21-Activated Kinase Inhibitors

  摘要：

  The p21-activated kinases (PAKs) play important roles in cytoskeletal organization, cellular morphogenesis, and survival and have generated significant attention as potential therapeutic targets for cancer. Following a high-throughput screen, we identified an aminopyrazole scaffold-based series that was optimized to yield group I selective PAK inhibitors. A structure-based design effort aimed at targeting the ribose pocket for both potency and selectivity led to much-improved group I vs II selectivity. Early lead compounds contained a basic primary amine, which was found to be a major metabolic soft spot with in vivo clearance proceeding predominantly via N-acetylation. We succeeded in identifying replacements with improved metabolic stability, leading to compounds with lower in vivo rodent clearance and excellent group I PAK selectivity.

  DOI：

  10.1021/acs.jmedchem.5b00572

文献信息

• Structure-Guided Design of Group I Selective p21-Activated Kinase Inhibitors
  作者：James J. Crawford、Wendy Lee、Ignacio Aliagas、Simon Mathieu、Klaus P. Hoeflich、Wei Zhou、Weiru Wang、Lionel Rouge、Lesley Murray、Hank La、Ning Liu、Peter W. Fan、Jonathan Cheong、Christopher E. Heise、Sreemathy Ramaswamy、Robert Mintzer、Yanzhou Liu、Qi Chao、Joachim Rudolph

  DOI：10.1021/acs.jmedchem.5b00572

  日期：2015.6.25

  The p21-activated kinases (PAKs) play important roles in cytoskeletal organization, cellular morphogenesis, and survival and have generated significant attention as potential therapeutic targets for cancer. Following a high-throughput screen, we identified an aminopyrazole scaffold-based series that was optimized to yield group I selective PAK inhibitors. A structure-based design effort aimed at targeting the ribose pocket for both potency and selectivity led to much-improved group I vs II selectivity. Early lead compounds contained a basic primary amine, which was found to be a major metabolic soft spot with in vivo clearance proceeding predominantly via N-acetylation. We succeeded in identifying replacements with improved metabolic stability, leading to compounds with lower in vivo rodent clearance and excellent group I PAK selectivity.