(2R,3R)-3-[6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)pyrazin-2-ylamino]-2-(4-fluorophenyl)pyrrolidine-1-carbaldehyde | 1350821-45-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: (2R,3R)-3-[6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)pyrazin-2-ylamino]-2-(4-fluorophenyl)pyrrolidine-1-carbaldehyde
• 英文别名: (2R,3R)-3-[[6-(4-amino-7-propan-2-ylpyrrolo[2,3-d]pyrimidine-5-carbonyl)pyrazin-2-yl]amino]-2-(4-fluorophenyl)pyrrolidine-1-carbaldehyde
• CAS: 1350821-45-2
• 化学式: C₂₅H₂₅FN₈O₂
• 分子量: 488.524
• InChiKey: TZOLUHQWLXJGBH-XMSQKQJNSA-N

物化性质

• 沸点：
  781.2±60.0 °C(Predicted)
• 密度：
  1.48±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  36
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  132
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  (2R,3R)-3-[6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)pyrazin-2-ylamino]-2-(4-fluorophenyl)pyrrolidine-1-carbaldehyde 在 盐酸 、 水 作用下， 以 甲醇 为溶剂， 生成 (4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl){6-[(2R,3R)-2-(4-fluorophenyl)pyrrolidin-3-ylamino]pyrazin-2-yl}methanone formate
  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
• 作为产物：
  描述：

  6-chloropyrazine-2-carboxylic acid methoxymethylamide 在 甲醇 、 正丁基锂 、 氨 、 caesium carbonate 、 N,N-二异丙基乙胺 、 cesium fluoride 作用下， 以 甲醇 、 乙醚 、 正己烷 、 异丁酰胺 、 二甲基亚砜 为溶剂， 反应 42.0h， 生成 (2R,3R)-3-[6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)pyrazin-2-ylamino]-2-(4-fluorophenyl)pyrrolidine-1-carbaldehyde
  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

文献信息

• Discovery of Novel, Potent, and Selective Inhibitors of 3-Phosphoinositide-Dependent Kinase (PDK1)
  作者：Sean T. Murphy、Gordon Alton、Simon Bailey、Sangita M. Baxi、Benjamin J. Burke、Thomas A. Chappie、Jacques Ermolieff、RoseAnn Ferre、Samantha Greasley、Michael Hickey、John Humphrey、Natasha Kablaoui、John Kath、Steven Kazmirski、Michelle Kraus、Stan Kupchinsky、John Li、Laura Lingardo、Matthew A. Marx、Dan Richter、Steven P. Tanis、Khanh Tran、William Vernier、Zhi Xie、Min-Jean Yin、Xiao-Hong Yu

  DOI：10.1021/jm201019k

  日期：2011.12.22

  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.