[4-amino-7-(propan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl](6-{[(1R,2R)-2-phenylcyclopentyl]amino}pyrazin-2-yl)methanone | 1350821-36-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: [4-amino-7-(propan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl](6-{[(1R,2R)-2-phenylcyclopentyl]amino}pyrazin-2-yl)methanone
• 英文别名: (4-amino-7-propan-2-ylpyrrolo[2,3-d]pyrimidin-5-yl)-[6-[[(1R,2R)-2-phenylcyclopentyl]amino]pyrazin-2-yl]methanone
• CAS: 1350821-36-1
• 化学式: C₂₅H₂₇N₇O
• 分子量: 441.536
• InChiKey: DINCQWMGMYFLCH-IEBWSBKVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  33
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  112
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  trans-2-phenylcyclopentan-1-ol 在 偶氮二甲酸二异丙酯 、 N,N-二异丙基乙胺 、 三苯基膦 、 cesium fluoride 、 肼 作用下， 以 四氢呋喃 、 二甲基亚砜 、 甲苯 为溶剂， 反应 16.0h， 生成 [4-amino-7-(propan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl](6-{[(1R,2R)-2-phenylcyclopentyl]amino}pyrazin-2-yl)methanone 、 [4-amino-7-(propan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl](6-{[(1S,2S)-2-phenylcyclopentyl]amino}pyrazin-2-yl)-methanone
  参考文献：
  名称：

  Discovery of Novel, Potent, and Selective Inhibitors of 3-Phosphoinositide-Dependent Kinase (PDK1)

  摘要：

  Analogues substituted with various amines at the 6-position of the pyrazine ring on (4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrazin-2-ylmethanone were discovered as potent and selective inhibitors of PDK1 with potential as anticancer agents. An early lead with 2-pyridine-3-ylethylamine as the pyrazine substituent showed moderate potency and selectivity. Structure-based drug design led to improved potency and selectivity against PI3K alpha through a combination of cyclizing the ethylene spacer into a saturated, five-membered ring and substituting on the 4-position of the aryl ring with a fluorine. ADME properties were improved by lowering the lipophilicity with heteroatom replacements in the saturated, five-membered ring. The optimized analogues have a PDK1 K-i of 1 nM and >100-fold selectivity against PI3K/AKT-pathway kinases. The cellular potency of these analogues was assessed by the inhibition of AKT phosphorylation (T308) and by their antiproliferation activity against a number of tumor cell lines.

  DOI：

  10.1021/jm201019k