N²-((4-chloro-1H-benzo[d]imidazol-5-yl)methyl)-N⁴-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-methylpyrimidine-2,4-diamine | 1425929-74-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: N²-((4-chloro-1H-benzo[d]imidazol-5-yl)methyl)-N⁴-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-methylpyrimidine-2,4-diamine
• 英文别名: 2-N-[(4-chloro-1H-benzimidazol-5-yl)methyl]-4-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-N-methylpyrimidine-2,4-diamine
• CAS: 1425929-74-3
• 化学式: C₁₉H₁₉ClN₈
• 分子量: 394.866
• InChiKey: LDWBULFGVRAVMR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  98.4
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  6-溴-7-氯-1H-苯并咪唑 在 盐酸 、 1,1'-双(二苯基膦)二茂铁 、 tris-(dibenzylideneacetone)dipalladium(0) 、 camphor-10-sulfonic acid 、 氨 、 氢气 、 镍 、 sodium hydride 、 对甲苯磺酸 、 N,N-二异丙基乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 水 、 N,N-二甲基甲酰胺 、 mineral oil 、 正丁醇 为溶剂， 反应 62.42h， 生成 N²-((4-chloro-1H-benzo[d]imidazol-5-yl)methyl)-N⁴-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-methylpyrimidine-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

• SERINE/THREONINE KINASE INHIBITORS
  申请人：Aliagas-Martin Ignacio

  公开号：US20130225620A1

  公开（公告）日：2013-08-29

  Compounds having the formula I wherein A, Z, R 1a , R 1b , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , R a , R b and n are as defined herein are inhibitors of PAK1. Also disclosed are compositions and methods for treating cancer and hyperproliferative disorders.

  具有公式I的化合物，其中A，Z，R1a，R1b，R2，R3，R4，R5，R6，R7，R9，R10，Ra，Rb和n的定义如本文所述，是PAK1的抑制剂。还公开了治疗癌症和高增殖性疾病的组合物和方法。
• US8637537B2
  申请人：——

  公开号：US8637537B2

  公开（公告）日：2014-01-28
• 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.