2-((3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)amino)-2-oxoethyl 2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)acetate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 2-((3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)amino)-2-oxoethyl 2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)acetate
• 英文别名: [2-[(3,5-dimethyl-1-phenylpyrazol-4-yl)amino]-2-oxoethyl] 2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)acetate
• 化学式: C₂₃H₂₃N₅O₃
• 分子量: 417.467
• InChiKey: DERQSLKOSNFTHX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  31
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  102
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  3,5-二甲基-4-硝基吡唑 在 trans-N,N'-dimethyl-1,2-cyclohexyldiamine 、 甲醇 、 4-二甲氨基吡啶 、 copper(l) iodide 、 palladium 10% on activated carbon 、 氢气 、 sodium methylate 、 potassium carbonate 、 三乙胺 、 N,N'-二环己基碳二亚胺 作用下， 以 乙醇 、 二氯甲烷 、 氯仿 、 乙腈 为溶剂， -10.0~180.0 ℃ 、405.33 kPa 条件下， 反应 63.0h， 生成 2-((3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)amino)-2-oxoethyl 2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)acetate
  参考文献：
  名称：

  Depsipeptides Featuring a Neutral P1 Are Potent Inhibitors of Kallikrein-Related Peptidase 6 with On-Target Cellular Activity

  摘要：

  Kallikrein-related peptidase 6 (KLK6) is a secreted serine protease that belongs to the family of tissue kallikreins (KLKs). Many KLKs are investigated as potential biomarkers for cancer as well as therapeutic drug targets for a number of pathologies. KLK6, in particular, has been implicated in neurodegenerative diseases and cancer, but target validation has been hampered by a lack of selective inhibitors. This work introduces a class of depsipeptidic KLK6 inhibitors, discovered via high-throughput screening, which were found to function as substrate mimics that transiently acylate the catalytic serine of KLK6. Detailed structure-activity relationship studies, aided by in silico modeling, uncovered strict structural requirements for potency, stability, and acyl-enzyme complex half-life. An optimized scaffold, DKFZ-251, demonstrated good selectivity for KLK6 compared to other KLKs, and on-target activity in a cellular assay. Moreover, DKFZ-633, an inhibitor-derived activity based probe, could be used to pull down active endogenous KLK6.

  DOI：

  10.1021/acs.jmedchem.8b01106