2-({2-[1-(4-isobutylphenyl)ethyl]-1H-benzimidazol-1-yl}methyl)phenol | 1382487-84-4

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 英文名称: 2-({2-[1-(4-isobutylphenyl)ethyl]-1H-benzimidazol-1-yl}methyl)phenol
• 英文别名: 2-[[2-[1-[4-(2-Methylpropyl)phenyl]ethyl]benzimidazol-1-yl]methyl]phenol
• CAS: 1382487-84-4
• 化学式: C₂₆H₂₈N₂O
• 分子量: 384.521
• InChiKey: MQAVCVGDMLXZFA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.6
• 重原子数：
  29
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  38
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  2-({2-[1-(4-isobutylphenyl)ethyl]-1H-benzimidazol-1-yl}methyl)phenol 在 potassium carbonate 、 lithium hydroxide 作用下， 以 四氢呋喃 、 水 、 乙腈 为溶剂， 反应 2.5h， 生成
  参考文献：
  名称：

  The novel benzimidazole derivative BRP-7 inhibits leukotriene biosynthesisin vitroandin vivoby targeting 5-lipoxygenase-activating protein (FLAP)

  摘要：

  Background and PurposeLeukotrienes (LTs) are inflammatory mediators produced via the 5‐lipoxygenase (5‐LOX) pathway and are linked to diverse disorders, including asthma, allergic rhinitis and cardiovascular diseases. We recently identified the benzimidazole derivative BRP‐7 as chemotype for anti‐LT agents by virtual screening targeting 5‐LOX‐activating protein (FLAP). Here, we aimed to reveal the in vitro and in vivo pharmacology of BRP‐7 as an inhibitor of LT biosynthesis.Experimental ApproachWe analysed LT formation and performed mechanistic studies in human neutrophils and monocytes, in human whole blood (HWB) and in cell‐free assays. The effectiveness of BRP‐7 in vivo was evaluated in rat carrageenan‐induced pleurisy and mouse zymosan‐induced peritonitis.Key ResultsBRP‐7 potently suppressed LT formation in neutrophils and monocytes and this was accompanied by impaired 5‐LOX co‐localization with FLAP. Neither the cellular viability nor the activity of 5‐LOX in cell‐free assays was affected by BRP‐7, indicating that a functional FLAP is needed for BRP‐7 to inhibit LTs, and FLAP bound to BRP‐7 linked to a solid matrix. Compared with the FLAP inhibitor MK‐886, BRP‐7 did not significantly inhibit COX‐1 or microsomal prostaglandin E2 synthase‐1, implying the selectivity of BRP‐7 for FLAP. Finally, BRP‐7 was effective in HWB and impaired inflammation in vivo, in rat pleurisy and mouse peritonitis, along with reducing LT levels.Conclusions and ImplicationsBRP‐7 potently suppresses LT biosynthesis by interacting with FLAP and exhibits anti‐inflammatory effectiveness in vivo, with promising potential for further development.

  DOI：

  10.1111/bph.12625
• 作为产物：
  描述：

  N-(2-aminophenyl)-2-(4-isobutylphenyl)propanamide 在 溶剂黄146 作用下， 反应 4.0h， 生成 2-({2-[1-(4-isobutylphenyl)ethyl]-1H-benzimidazol-1-yl}methyl)phenol
  参考文献：
  名称：

  Identification of novel benzimidazole derivatives as inhibitors of leukotriene biosynthesis by virtual screening targeting 5-lipoxygenase-activating protein (FLAP)

  摘要：

  Pharmacological suppression of leukotriene biosynthesis by 5-lipoxygenase (5-LO)-activating protein (FLAP) inhibitors is a promising strategy to intervene with inflammatory, allergic and cardiovascular diseases. Virtual screening targeting FLAP based on a combined ligand-and structure-based pharmacophore model led to the identification of 1-(2-chlorobenzyl)-2-(1-(4-isobutylphenyl)ethyl)-1H-benzimidazole (7) as developable candidate. Compound 7 potently suppressed leukotriene formation in intact neutrophils (IC50 = 0.31 mu M) but essentially failed to directly inhibit 5-LO suggesting that interaction with FLAP causes inhibition of leukotriene synthesis. For structural optimization, a series of 46 benzimidazole-based derivatives of 7 were synthesized leading to more potent analogues (70-72, 82) with IC50 = 0.12-0.19 mu M in intact neutrophils. Together, our results disclose the benzimidazole scaffold bearing an ibuprofen fingerprint as a new chemotype for further development of anti-leukotriene agents. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.04.048

文献信息

• Identification of novel benzimidazole derivatives as inhibitors of leukotriene biosynthesis by virtual screening targeting 5-lipoxygenase-activating protein (FLAP)
  作者：Erden Banoglu、Burcu Çalışkan、Susann Luderer、Gökçen Eren、Yagmur Özkan、Wolfram Altenhofen、Christina Weinigel、Dagmar Barz、Jana Gerstmeier、Carlo Pergola、Oliver Werz

  DOI：10.1016/j.bmc.2012.04.048

  日期：2012.6

  Pharmacological suppression of leukotriene biosynthesis by 5-lipoxygenase (5-LO)-activating protein (FLAP) inhibitors is a promising strategy to intervene with inflammatory, allergic and cardiovascular diseases. Virtual screening targeting FLAP based on a combined ligand-and structure-based pharmacophore model led to the identification of 1-(2-chlorobenzyl)-2-(1-(4-isobutylphenyl)ethyl)-1H-benzimidazole (7) as developable candidate. Compound 7 potently suppressed leukotriene formation in intact neutrophils (IC50 = 0.31 mu M) but essentially failed to directly inhibit 5-LO suggesting that interaction with FLAP causes inhibition of leukotriene synthesis. For structural optimization, a series of 46 benzimidazole-based derivatives of 7 were synthesized leading to more potent analogues (70-72, 82) with IC50 = 0.12-0.19 mu M in intact neutrophils. Together, our results disclose the benzimidazole scaffold bearing an ibuprofen fingerprint as a new chemotype for further development of anti-leukotriene agents. (C) 2012 Elsevier Ltd. All rights reserved.
• The novel benzimidazole derivative BRP-7 inhibits leukotriene biosynthesis<i>in vitro</i>and<i>in vivo</i>by targeting 5-lipoxygenase-activating protein (FLAP)
  作者：C Pergola、J Gerstmeier、B Mönch、B Çalışkan、S Luderer、C Weinigel、D Barz、J Maczewsky、S Pace、A Rossi、L Sautebin、E Banoglu、O Werz

  DOI：10.1111/bph.12625

  日期：2014.6

  Background and PurposeLeukotrienes (LTs) are inflammatory mediators produced via the 5‐lipoxygenase (5‐LOX) pathway and are linked to diverse disorders, including asthma, allergic rhinitis and cardiovascular diseases. We recently identified the benzimidazole derivative BRP‐7 as chemotype for anti‐LT agents by virtual screening targeting 5‐LOX‐activating protein (FLAP). Here, we aimed to reveal the in vitro and in vivo pharmacology of BRP‐7 as an inhibitor of LT biosynthesis.Experimental ApproachWe analysed LT formation and performed mechanistic studies in human neutrophils and monocytes, in human whole blood (HWB) and in cell‐free assays. The effectiveness of BRP‐7 in vivo was evaluated in rat carrageenan‐induced pleurisy and mouse zymosan‐induced peritonitis.Key ResultsBRP‐7 potently suppressed LT formation in neutrophils and monocytes and this was accompanied by impaired 5‐LOX co‐localization with FLAP. Neither the cellular viability nor the activity of 5‐LOX in cell‐free assays was affected by BRP‐7, indicating that a functional FLAP is needed for BRP‐7 to inhibit LTs, and FLAP bound to BRP‐7 linked to a solid matrix. Compared with the FLAP inhibitor MK‐886, BRP‐7 did not significantly inhibit COX‐1 or microsomal prostaglandin E2 synthase‐1, implying the selectivity of BRP‐7 for FLAP. Finally, BRP‐7 was effective in HWB and impaired inflammation in vivo, in rat pleurisy and mouse peritonitis, along with reducing LT levels.Conclusions and ImplicationsBRP‐7 potently suppresses LT biosynthesis by interacting with FLAP and exhibits anti‐inflammatory effectiveness in vivo, with promising potential for further development.