phenyl (4-cyano-2-fluorophenyl)carbamate

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: phenyl (4-cyano-2-fluorophenyl)carbamate
• 英文别名: phenyl N-(4-cyano-2-fluorophenyl)carbamate
• 化学式: C₁₄H₉FN₂O₂
• 分子量: 256.236
• InChiKey: CPYMFGBFNLZDMN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  19
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  62.1
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  trans-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine 、 phenyl (4-cyano-2-fluorophenyl)carbamate 在 吡啶 作用下， 反应 4.0h， 以47%的产率得到1-(4-cyano-2-fluorophenyl)-3-(trans-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)urea
  参考文献：
  名称：

  New activators of eIF2α Kinase Heme-Regulated Inhibitor (HRI) with improved biophysical properties

  摘要：

  Heme-regulated inhibitor (HRI), a eukaryotic translation initiation factor 2 alpha (eIF2 alpha) kinase, is critically important for coupling protein synthesis to heme availability in reticulocytes and adaptation to various environmental stressors in all cells. HRI modifies the severity of several hemoglobin misfolding disorders including beta-thalassemia. Small molecule activators of HRI are essential for studying normaland patho-biology of this kinase as well as for the treatment of various human disorders for which activation of HRI or phosphorylation of eIF2 alpha may be beneficial. We previously reported development of 14(1,4-trans)-4-aryloxycyclohexyl)-3-arylureas (cHAUs) as specific HRI activators and demonstrated their potential as molecular probes for studying HRI biology and as lead compounds for treatment of various human disorders. To develop more druglike cHAUs for in vivo studies and drug development and to expand the chemical space, we undertook bioassay guided structure-activity relationship studies replacing cyclohexyl ring with various 4-6-membered rings and explored further substitutions on the N-phenyl ring. We tested all analogs in the surrogate eIF2 alpha phosphorylation and cell proliferation assays, and a subset of analogs in secondary mechanistic assays that included endogenous eIF2 alpha phosphorylation and expression of C/EBP homologous protein (CHOP), a downstream effector. Finally, we determined specificity of these compounds for HRI by testing their anti-proliferative activity in cells transfected with siRNA targeting HRI or mock. These compounds have significantly improved cLogPs with no loss of potencies, making them excellent candidates for lead optimization for development of investigational new drugs that potently and specifically activate HRI. (C) 2019 Published by Elsevier Masson SAS.

  DOI：

  10.1016/j.ejmech.2019.111973
• 作为产物：
  描述：

  3-氟-4-氨基苯腈 、 氯甲酸苯酯 在 吡啶 作用下， 以 二氯甲烷 为溶剂， 反应 4.0h， 生成 phenyl (4-cyano-2-fluorophenyl)carbamate
  参考文献：
  名称：

  New activators of eIF2α Kinase Heme-Regulated Inhibitor (HRI) with improved biophysical properties

  摘要：

  Heme-regulated inhibitor (HRI), a eukaryotic translation initiation factor 2 alpha (eIF2 alpha) kinase, is critically important for coupling protein synthesis to heme availability in reticulocytes and adaptation to various environmental stressors in all cells. HRI modifies the severity of several hemoglobin misfolding disorders including beta-thalassemia. Small molecule activators of HRI are essential for studying normaland patho-biology of this kinase as well as for the treatment of various human disorders for which activation of HRI or phosphorylation of eIF2 alpha may be beneficial. We previously reported development of 14(1,4-trans)-4-aryloxycyclohexyl)-3-arylureas (cHAUs) as specific HRI activators and demonstrated their potential as molecular probes for studying HRI biology and as lead compounds for treatment of various human disorders. To develop more druglike cHAUs for in vivo studies and drug development and to expand the chemical space, we undertook bioassay guided structure-activity relationship studies replacing cyclohexyl ring with various 4-6-membered rings and explored further substitutions on the N-phenyl ring. We tested all analogs in the surrogate eIF2 alpha phosphorylation and cell proliferation assays, and a subset of analogs in secondary mechanistic assays that included endogenous eIF2 alpha phosphorylation and expression of C/EBP homologous protein (CHOP), a downstream effector. Finally, we determined specificity of these compounds for HRI by testing their anti-proliferative activity in cells transfected with siRNA targeting HRI or mock. These compounds have significantly improved cLogPs with no loss of potencies, making them excellent candidates for lead optimization for development of investigational new drugs that potently and specifically activate HRI. (C) 2019 Published by Elsevier Masson SAS.

  DOI：

  10.1016/j.ejmech.2019.111973

文献信息

• IDO INHIBITORS
  申请人：BRISTOL-MYERS SQUIBB COMPANY

  公开号：US20160289171A1

  公开（公告）日：2016-10-06

  There are disclosed compounds that modulate or inhibit the enzymatic activity of indoleamine 2,3-dioxygenase (IDO), pharmaceutical compositions containing said compounds and methods of treating proliferative disorders, such as cancer, viral infections and/or inflammatory disorders utilizing the compounds of the invention.

  已披露的化合物可调节或抑制吲哌酮胺2,3-二氧化酶（IDO）的酶活性，含有该化合物的药物组合物以及利用本发明的化合物治疗增殖性疾病，如癌症、病毒感染和/或炎症性疾病的方法。
• [EN] IDO INHIBITORS<br/>[FR] INHIBITEURS D'IDO
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2016210414A1

  公开（公告）日：2016-12-29

  There are disclosed compounds that modulate or inhibit the enzymatic activity of indoleamine 2,3-dioxygenase (IDO), pharmaceutical compositions containing said compounds and methods of treating proliferative disorders, such as cancer, viral infections and/or inflammatory disorders utilizing the compounds of the invention.

  本文揭示了一些化合物，可以调节或抑制色氨酸2,3-二氧化酶（IDO）的酶活性，含有这些化合物的药物组合物以及利用本发明的化合物治疗增生性疾病（如癌症、病毒感染和/或炎症性疾病）的方法。
• New activators of eIF2α Kinase Heme-Regulated Inhibitor (HRI) with improved biophysical properties
  作者：Qingwen Zhang、Ronghui Du、Guilherme Rodrigo Reis Monteiro dos Santos、Revital Yefidoff-Freedman、Andrew Bohm、Jose Halperin、Michael Chorev、Bertal H. Aktas

  DOI：10.1016/j.ejmech.2019.111973

  日期：2020.2

  Heme-regulated inhibitor (HRI), a eukaryotic translation initiation factor 2 alpha (eIF2 alpha) kinase, is critically important for coupling protein synthesis to heme availability in reticulocytes and adaptation to various environmental stressors in all cells. HRI modifies the severity of several hemoglobin misfolding disorders including beta-thalassemia. Small molecule activators of HRI are essential for studying normaland patho-biology of this kinase as well as for the treatment of various human disorders for which activation of HRI or phosphorylation of eIF2 alpha may be beneficial. We previously reported development of 14(1,4-trans)-4-aryloxycyclohexyl)-3-arylureas (cHAUs) as specific HRI activators and demonstrated their potential as molecular probes for studying HRI biology and as lead compounds for treatment of various human disorders. To develop more druglike cHAUs for in vivo studies and drug development and to expand the chemical space, we undertook bioassay guided structure-activity relationship studies replacing cyclohexyl ring with various 4-6-membered rings and explored further substitutions on the N-phenyl ring. We tested all analogs in the surrogate eIF2 alpha phosphorylation and cell proliferation assays, and a subset of analogs in secondary mechanistic assays that included endogenous eIF2 alpha phosphorylation and expression of C/EBP homologous protein (CHOP), a downstream effector. Finally, we determined specificity of these compounds for HRI by testing their anti-proliferative activity in cells transfected with siRNA targeting HRI or mock. These compounds have significantly improved cLogPs with no loss of potencies, making them excellent candidates for lead optimization for development of investigational new drugs that potently and specifically activate HRI. (C) 2019 Published by Elsevier Masson SAS.