4-(2-bromo-6-fluorobenzoyl)-N-(pyridin-3-yl)-1H-pyrrole-2-carboxamide

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 4-(2-bromo-6-fluorobenzoyl)-N-(pyridin-3-yl)-1H-pyrrole-2-carboxamide
• 英文别名: Erk5-IN-2；4-(2-bromo-6-fluorobenzoyl)-N-pyridin-3-yl-1H-pyrrole-2-carboxamide
• 化学式: C₁₇H₁₁BrFN₃O₂
• 分子量: 388.196
• InChiKey: ATKCERYALDNMPL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  24
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  74.8
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  2-吡咯甲酸甲酯 在 aluminum (III) chloride 、 lithium hydroxide 、 三氯化磷 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 乙腈 为溶剂， 反应 34.08h， 生成 4-(2-bromo-6-fluorobenzoyl)-N-(pyridin-3-yl)-1H-pyrrole-2-carboxamide
  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

• [EN] PYRROLCARBOXAMIDE DERIVATIVES FOR THE INHBITION OF ERK5<br/>[FR] DÉRIVÉS DE PYRROLCARBOXAMIDE POUR L'INHIBITION DE L'ERK5
  申请人：CANCER REC TECH LTD

  公开号：WO2016042341A1

  公开（公告）日：2016-03-24

  The invention provides compounds of formula (I) or a tautomer, stereoisomer, N-oxide, pharmaceutically acceptable salt or solvate thereof. The compounds are useful for the prophylaxis or treatment of a disease state or condition mediated by ERK5, in particular cancers.

  这项发明提供了式(I)的化合物或其互变异构体、立体异构体、N-氧化物、药用可接受的盐或溶剂。这些化合物对于预防或治疗由ERK5介导的疾病状态或病况，特别是癌症，具有用处。
• Pyrrolcarboxamide derivatives for the inhibition of ERK5
  申请人：CANCER RESEARCH TECHNOLOGY LIMITED

  公开号：US10344017B2

  公开（公告）日：2019-07-09

  The invention provides compounds of formula (I) or a tautomer, stereoisomer, N-oxide, pharmaceutically acceptable salt or solvate thereof. The compounds are useful for the prophylaxis or treatment of a disease state or condition mediated by ERK5, in particular cancers.

  本发明提供了式 (I) 的化合物 或其同系物、立体异构体、N-氧化物、药学上可接受的盐或溶液。这些化合物可用于预防或治疗由 ERK5 介导的疾病状态或病症，尤其是癌症。
• PYRROLCARBOXAMIDE DERIVATIVES FOR THE INHBITION OF ERK5
  申请人：Cancer Research Technology Ltd

  公开号：EP3194390A1

  公开（公告）日：2017-07-26
• PYRROLCARBOXAMIDE DERIVATIVES FOR THE INHIBITION OF ERK5
  申请人：CANCER RESEARCH TECHNOLOGY LIMITED

  公开号：US20180170911A1

  公开（公告）日：2018-06-21

  The invention provides compounds of formula (I) or a tautomer, stereoisomer, N-oxide, pharmaceutically acceptable salt or solvate thereof. The compounds are useful for the prophylaxis or treatment of a disease state or condition mediated by ERK5, in particular cancers.
• 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.