N-(cyclohexylmethyl)-2-{1-oxo-7-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl}acetamide | 1218806-45-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: N-(cyclohexylmethyl)-2-{1-oxo-7-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl}acetamide
• 英文别名: N-(cyclohexylmethyl)-2-[1-oxo-7-[3-(trifluoromethyl)phenyl]-3,4-dihydro-2H-pyrrolo[1,2-a]pyrazin-4-yl]acetamide
• CAS: 1218806-45-1
• 化学式: C₂₃H₂₆F₃N₃O₂
• 分子量: 433.474
• InChiKey: PKRBTUYJUUCTBM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  31
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  63.1
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  ethyl {1-oxo-7-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl}acetate 在 水 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 、 lithium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 为溶剂， 反应 22.25h， 生成 N-(cyclohexylmethyl)-2-{1-oxo-7-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl}acetamide
  参考文献：
  名称：

  Discovery and optimization of pyrrolo[1,2-a]pyrazinones leads to novel and selective inhibitors of PIM kinases

  摘要：

  A novel series of PIM inhibitors was derived from a combined effort in natural product-inspired library generation and screening. The novel pyrrolo[1,2-a]pyrazinones initial hits are inhibitors of PIM isoforms with IC50 values in the low micromolar range. The application of a rational optimization strategy, guided by the determination of the crystal structure of the complex in the kinase domain of PIM1 with compound 1, led to the discovery of compound 15a, which is a potent PIM kinases inhibitor exhibiting excellent selectivity against a large panel of kinases, representative of each family. The synthesis, structure-activity relationship studies, and pharmacokinetic data of compounds from this inhibitor class are presented herein. Furthermore, the cellular activities including inhibition of cell growth and modulation of downstream targets are also described. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.09.054

文献信息

• Discovery and optimization of pyrrolo[1,2-a]pyrazinones leads to novel and selective inhibitors of PIM kinases
  作者：Francesco Casuscelli、Elena Ardini、Nilla Avanzi、Elena Casale、Giovanni Cervi、Matteo D’Anello、Daniele Donati、Daniela Faiardi、Ronald D. Ferguson、Gianpaolo Fogliatto、Arturo Galvani、Aurelio Marsiglio、Danilo G. Mirizzi、Marisa Montemartini、Christian Orrenius、Gianluca Papeo、Claudia Piutti、Barbara Salom、Eduard R. Felder

  DOI：10.1016/j.bmc.2013.09.054

  日期：2013.12

  A novel series of PIM inhibitors was derived from a combined effort in natural product-inspired library generation and screening. The novel pyrrolo[1,2-a]pyrazinones initial hits are inhibitors of PIM isoforms with IC50 values in the low micromolar range. The application of a rational optimization strategy, guided by the determination of the crystal structure of the complex in the kinase domain of PIM1 with compound 1, led to the discovery of compound 15a, which is a potent PIM kinases inhibitor exhibiting excellent selectivity against a large panel of kinases, representative of each family. The synthesis, structure-activity relationship studies, and pharmacokinetic data of compounds from this inhibitor class are presented herein. Furthermore, the cellular activities including inhibition of cell growth and modulation of downstream targets are also described. (C) 2013 Elsevier Ltd. All rights reserved.