methyl 4-(2,6-dichlorobenzoyl)-1H-pyrrole-2-carboxylate

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: methyl 4-(2,6-dichlorobenzoyl)-1H-pyrrole-2-carboxylate
• 化学式: C₁₃H₉Cl₂NO₃
• 分子量: 298.125
• InChiKey: QMAZCLVVMADIGU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  19
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  59.2
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  methyl 4-(2,6-dichlorobenzoyl)-1H-pyrrole-2-carboxylate 在 lithium hydroxide 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 18.0h， 以93%的产率得到4-(2,6-dichlorobenzoyl)-1H-pyrrole-2-carboxylic acid
  参考文献：
  名称：

  Identification of a novel orally bioavailable ERK5 inhibitor with selectivity over p38α and BRD4

  摘要：

  Extracellular regulated kinase 5 (ERK5) signalling has been implicated in driving a number of cellular phenotypes including endothelial cell angiogenesis and tumour cell motility. Novel ERK5 inhibitors were identified using high throughput screening, with a series of pyrrole-2-carboxamides substituted at the 4 position with an aroyl group being found to exhibit 1050 values in the micromolar range, but having no selectivity against p38 alpha MAP kinase. Truncation of the N-substituent marginally enhanced potency (similar to 3-fold) against ERK5, but importantly attenuated inhibition of p38 alpha. Systematic variation of the substituents on the aroyl group led to the selective inhibitor 4-(2-bromo-6-fluorobenzoy1)-N-(pyridin-3-yl)-1H-pyrrole-2-carboxamide (IC50 0.82 mu M for ERK5; IC50 > 120 mu M for p38 alpha). The crystal structure (PDB 5071) of this compound in complex with ERK5 has been solved. This compound was orally bioavailable and inhibited bFGF-driven Matrigel plug angiogenesis and tumour xenograft growth. The selective ERK5 inhibitor described herein provides a lead for further development into a tool compound for more extensive studies seeking to examine the role of ERK5 signalling in cancer and other diseases. (C) 2019 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2019.05.057
• 作为产物：
  描述：

  2-吡咯甲酸甲酯 、 2,6-二氯苯甲酰氯 在 aluminum (III) chloride 作用下， 以 二氯甲烷 为溶剂， 反应 16.0h， 以73%的产率得到methyl 4-(2,6-dichlorobenzoyl)-1H-pyrrole-2-carboxylate
  参考文献：
  名称：

  Identification of a novel orally bioavailable ERK5 inhibitor with selectivity over p38α and BRD4

  摘要：

  Extracellular regulated kinase 5 (ERK5) signalling has been implicated in driving a number of cellular phenotypes including endothelial cell angiogenesis and tumour cell motility. Novel ERK5 inhibitors were identified using high throughput screening, with a series of pyrrole-2-carboxamides substituted at the 4 position with an aroyl group being found to exhibit 1050 values in the micromolar range, but having no selectivity against p38 alpha MAP kinase. Truncation of the N-substituent marginally enhanced potency (similar to 3-fold) against ERK5, but importantly attenuated inhibition of p38 alpha. Systematic variation of the substituents on the aroyl group led to the selective inhibitor 4-(2-bromo-6-fluorobenzoy1)-N-(pyridin-3-yl)-1H-pyrrole-2-carboxamide (IC50 0.82 mu M for ERK5; IC50 > 120 mu M for p38 alpha). The crystal structure (PDB 5071) of this compound in complex with ERK5 has been solved. This compound was orally bioavailable and inhibited bFGF-driven Matrigel plug angiogenesis and tumour xenograft growth. The selective ERK5 inhibitor described herein provides a lead for further development into a tool compound for more extensive studies seeking to examine the role of ERK5 signalling in cancer and other diseases. (C) 2019 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2019.05.057

文献信息

• Identification of a novel orally bioavailable ERK5 inhibitor with selectivity over p38α and BRD4
  作者：Stephanie M. Myers、Duncan C. Miller、Lauren Molyneux、Mercedes Arasta、Ruth H. Bawn、Timothy J. Blackburn、Simon J. Cook、Noel Edwards、Jane A. Endicott、Bernard T. Golding、Roger J. Griffin、Tim Hammonds、Ian R. Hardcastle、Suzannah J. Harnor、Amy B. Heptinstall、Pamela A. Lochhead、Mathew P. Martin、Nick C. Martin、David R. Newell、Paul J. Owen、Leon C. Pang、Tristan Reuillon、Laurent J.M. Rigoreau、Huw D. Thomas、Julie A. Tucker、Lan-Zhen Wang、Ai-Ching Wong、Martin E.M. Noble、Stephen R. Wedge、Celine Cano

  DOI：10.1016/j.ejmech.2019.05.057

  日期：2019.9

  Extracellular regulated kinase 5 (ERK5) signalling has been implicated in driving a number of cellular phenotypes including endothelial cell angiogenesis and tumour cell motility. Novel ERK5 inhibitors were identified using high throughput screening, with a series of pyrrole-2-carboxamides substituted at the 4 position with an aroyl group being found to exhibit 1050 values in the micromolar range, but having no selectivity against p38 alpha MAP kinase. Truncation of the N-substituent marginally enhanced potency (similar to 3-fold) against ERK5, but importantly attenuated inhibition of p38 alpha. Systematic variation of the substituents on the aroyl group led to the selective inhibitor 4-(2-bromo-6-fluorobenzoy1)-N-(pyridin-3-yl)-1H-pyrrole-2-carboxamide (IC50 0.82 mu M for ERK5; IC50 > 120 mu M for p38 alpha). The crystal structure (PDB 5071) of this compound in complex with ERK5 has been solved. This compound was orally bioavailable and inhibited bFGF-driven Matrigel plug angiogenesis and tumour xenograft growth. The selective ERK5 inhibitor described herein provides a lead for further development into a tool compound for more extensive studies seeking to examine the role of ERK5 signalling in cancer and other diseases. (C) 2019 Elsevier Masson SAS. All rights reserved.