4-(2,5-二氟苯基)-2-氟苯甲酸 | 1184513-36-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 4-(2,5-二氟苯基)-2-氟苯甲酸
• 英文名称: 2',3,5'-trifluoro-[1,1'-biphenyl]-4-carboxylic acid
• 英文别名: 4-(2,5-Difluorophenyl)-2-fluorobenzoic acid
• CAS: 1184513-36-7
• 化学式: C₁₃H₇F₃O₂
• 分子量: 252.193
• InChiKey: SVMOPWVECXWXKW-UHFFFAOYSA-N

物化性质

• 沸点：
  358.3±42.0 °C(Predicted)
• 密度：
  1.402±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  37.3
• 氢给体数：
  1
• 氢受体数：
  5

安全信息

• 海关编码：
  2916399090

反应信息

• 作为反应物：
  描述：

  (R)-2-amino-3-(1H-indol-3-yl)-N-(pyridin-4-yl)propanamide hydrochloric acid 、 4-(2,5-二氟苯基)-2-氟苯甲酸 在 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 1-羟基苯并三唑 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 1.25h， 以69%的产率得到(R)-N-(3-(1H-indol-3-yl)-1-oxo-1-(pyridin-4-ylamino)propan-2-yl)-2',3,5'-trifluoro-[1,1'-biphenyl]-4-carboxamide
  参考文献：
  名称：

  4-Aminopyridyl-Based CYP51 Inhibitors as Anti-Trypanosoma cruzi Drug Leads with Improved Pharmacokinetic Profile and in Vivo Potency

  摘要：

  CYP51 is a P450 enzyme involved in the biosynthesis of the sterol components of eukaryotic cell membranes. CYP51 inhibitors have been developed to treat infections caused by fungi, and more recently the protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease. To specifically optimize drug candidates for T. cruzi CYP51 (TcCYP51), we explored the structure activity relationship (SAR) of a N-indolyl-oxopyridinyl-4-aminopropanyl-based scaffold originally identified in a target-based screen. This scaffold evolved via medicinal chemistry to yield orally bioavailable leads with potent anti-T. cruzi activity in vivo. Using an animal model of infection with a transgenic T. cruzi Y luc strain expressing firefly luciferase, we prioritized the biaryl and N-arylpiperazine analogues by oral bioavailability and potency. The drug target complexes for both scaffold variants were characterized by X-ray structure analysis. Optimization of both binding mode and pharmacokinetic properties of these compounds led to potent inhibitors against experimental T. cruzi infection.

  DOI：

  10.1021/jm500448u
• 作为产物：
  描述：

  4-溴-2-氟苯甲酸 、 2,5-二氟苯硼酸 在 potassium phosphate 、 tris-(dibenzylideneacetone)dipalladium(0) 、 三环己基膦 作用下， 以 1,4-二氧六环 为溶剂， 反应 2.0h， 以89%的产率得到4-(2,5-二氟苯基)-2-氟苯甲酸
  参考文献：
  名称：

  R-Configuration of 4-Aminopyridyl-Based Inhibitors of CYP51 Confers Superior Efficacy Against Trypanosoma cruzi

  摘要：

  Sterol 14 alpha-demethylase (CYP51) is an important therapeutic target for fungal and parasitic infections due to its key role in the biosynthesis of ergosterol, an essential component of the cell membranes of these pathogenic organisms. We report the development of potent and selective D-tryptophan-derived inhibitors of T. cruzi CYP51. Structural information obtained from the cocrystal structure of CYP51 and (R)-2, which is >1000-fold more potent than its enantiomer (S)-1, was used to guide design of additional analogues. The in vitro efficacy data presented here for (R)-2 (R)-8, together with preliminary in vitro pharmacokinetic data suggest that this new CYP51 inhibitor scaffold series has potential to deliver drug candidates for treatment of T. cruzi infections.

  DOI：

  10.1021/ml500010m

文献信息

• [EN] NOVEL AGENTS TARGETING CYP51<br/>[FR] NOUVEAUX AGENTS CIBLANT CYP51
  申请人：SCRIPPS RESEARCH INST

  公开号：WO2015048306A1

  公开（公告）日：2015-04-02

  The invention provides inhibitors of a sterol C14-demethylase, a new series of 4- aminopyridyl-based lead inhibitors targeting Trypanosoma cruzi CYP51 (TcCYP51) developed using structure-based drug design as well as structure -property relationship (SPR) analyses. The screening hit starting point, LP 10 (KD < 42 nM; EC50 of 0.65 μΜ), has been optimized to give the potential leads that have low nanomolar binding affinity to TcCYP51 and significant activity against T. cruzi amastigotes cultured in human myoblasts. Many of the optimized compounds have improved microsome stability, and most are selective against the T. cruzi CYP51 relative to human CYPs 1A2, 2D6 and 3A4 (<50% inhibition at 1 μΜ). A rationale for the improvement of microsome stability and selectivity of inhibitors against human metabolic CYP enzymes is presented. In addition, the binding mode of several compounds of the invention with the T. brucei CYP51 (TbCYP51) ortholog has been characterized by x-ray structure analysis. Orally active compounds and their cyclodextrin complexes have been shown to be effective against Chagas-infected mice.

  该发明提供了一种甾醇C14-去甲基酶的抑制剂，这是一种新系列基于4-氨基吡啶的首选抑制剂，通过基于结构的药物设计以及结构-性质关系（SPR）分析来瞄准Trypanosoma cruzi CYP51（TcCYP51）而开发的。筛选起始点LP 10（KD < 42 nM；EC50为0.65 μΜ）已经经过优化，产生了具有低纳摩尔级别结合亲和力和对在人类肌细胞培养的T. cruzi游离体的显著活性的潜在首选抑制剂。许多经过优化的化合物具有改善的微粒体稳定性，大多数相对于人类CYPs 1A2、2D6和3A4对T. cruzi CYP51具有选择性（在1 μΜ下<50%的抑制）。提出了改善微粒体稳定性和抑制剂对人类代谢CYP酶的选择性的理由。此外，通过X射线结构分析表征了该发明的几种化合物与T. brucei CYP51（TbCYP51）同源物的结合方式。口服活性化合物及其环糊精复合物已被证明对克氏病感染的小鼠有效。
• Rational Development of 4-Aminopyridyl-Based Inhibitors Targeting Trypanosoma cruzi CYP51 as Anti-Chagas Agents
  作者：Jun Yong Choi、Claudia M. Calvet、Shamila S. Gunatilleke、Claudia Ruiz、Michael D. Cameron、James H. McKerrow、Larissa M. Podust、William R. Roush

  DOI：10.1021/jm401067s

  日期：2013.10.10

  A new series of 4-aminopyridyl-based lead inhibitors targeting Trypanosoma cruzi CYP51 (TcCYP51) has been developed using structure-based drug design as well as structure-property relationship (SPR) analyses. The screening hit starting point, LP10 (K-D <= 42 nM; EC50 = 0.65 mu M), has been optimized to give the potential leads 14t, 27i, 27q, 27r, and 27t, which have low-nanomolar binding affinity to TcCYR51 and significant activity against T. cruzi amastigotes cultured in human myoblasts (EC50 = 14-18 nM for 27i and 27r). Many of the optimized compounds have improved microsome stability, and most are selective against human CYPs 1A2, 2D6, and 3A4 (<50% inhibition at 1 mu M). A rationale for the improvement in microsome stability and selectivity of inhibitors against human metabolic CYP enzymes is presented. In addition, the binding mode of 14t with the Trypanosoma brucei CYP51 (TbCYP51) orthologue has been characterized by X-ray structure analysis.
• 4-Aminopyridyl-Based CYP51 Inhibitors as Anti-<i>Trypanosoma cruzi</i> Drug Leads with Improved Pharmacokinetic Profile and in Vivo Potency
  作者：Claudia M. Calvet、Debora F. Vieira、Jun Yong Choi、Danielle Kellar、Michael D. Cameron、Jair Lage Siqueira-Neto、Jiri Gut、Jonathan B. Johnston、Li Lin、Susan Khan、James H. McKerrow、William R. Roush、Larissa M. Podust

  DOI：10.1021/jm500448u

  日期：2014.8.28

  CYP51 is a P450 enzyme involved in the biosynthesis of the sterol components of eukaryotic cell membranes. CYP51 inhibitors have been developed to treat infections caused by fungi, and more recently the protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease. To specifically optimize drug candidates for T. cruzi CYP51 (TcCYP51), we explored the structure activity relationship (SAR) of a N-indolyl-oxopyridinyl-4-aminopropanyl-based scaffold originally identified in a target-based screen. This scaffold evolved via medicinal chemistry to yield orally bioavailable leads with potent anti-T. cruzi activity in vivo. Using an animal model of infection with a transgenic T. cruzi Y luc strain expressing firefly luciferase, we prioritized the biaryl and N-arylpiperazine analogues by oral bioavailability and potency. The drug target complexes for both scaffold variants were characterized by X-ray structure analysis. Optimization of both binding mode and pharmacokinetic properties of these compounds led to potent inhibitors against experimental T. cruzi infection.
• <i>R</i>-Configuration of 4-Aminopyridyl-Based Inhibitors of CYP51 Confers Superior Efficacy Against <i>Trypanosoma cruzi</i>
  作者：Jun Yong Choi、Claudia M. Calvet、Debora F. Vieira、Shamila S. Gunatilleke、Michael D. Cameron、James H. McKerrow、Larissa M. Podust、William R. Roush

  DOI：10.1021/ml500010m

  日期：2014.4.10

  Sterol 14 alpha-demethylase (CYP51) is an important therapeutic target for fungal and parasitic infections due to its key role in the biosynthesis of ergosterol, an essential component of the cell membranes of these pathogenic organisms. We report the development of potent and selective D-tryptophan-derived inhibitors of T. cruzi CYP51. Structural information obtained from the cocrystal structure of CYP51 and (R)-2, which is >1000-fold more potent than its enantiomer (S)-1, was used to guide design of additional analogues. The in vitro efficacy data presented here for (R)-2 (R)-8, together with preliminary in vitro pharmacokinetic data suggest that this new CYP51 inhibitor scaffold series has potential to deliver drug candidates for treatment of T. cruzi infections.