(2R,3S)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(4H-1,2,4-三唑-4-基)丁烷-2-醇 | 1028563-65-6

• 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: (2R,3S)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(4H-1,2,4-三唑-4-基)丁烷-2-醇
• 英文名称: (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(4H-1,2,4-triazol-4-yl)butan-2-ol
• 英文别名: (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1,2,4-triazol-4-yl)butan-2-ol
• CAS: 1028563-65-6
• 化学式: C₁₆H₁₄F₃N₅O
• 分子量: 349.315
• InChiKey: QRAMNBZTYLSISP-MGPLVRAMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  76.7
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  4-乙基-5-氟嘧啶 、 伏立康唑杂质49 在 lithium diisopropyl amide 作用下， 生成 (2R,3S)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(4H-1,2,4-三唑-4-基)丁烷-2-醇
  参考文献：
  名称：

  Design and optimization of highly-selective fungal CYP51 inhibitors

  摘要：

  While the orally-active azoles such as voriconazole and itraconazole are effective antifungal agents, they potently inhibit a broad range of off-target human cytochrome P450 enzymes (CYPs) leading to various safety issues (e.g., drug-drug interactions, liver toxicity). Herein, we describe rationally-designed, broad-spectrum antifungal agents that are more selective for the target fungal enzyme, CYP51, than related human CYP enzymes such as CYP3A4. Using proprietary methodology, the triazole metal-binding group found in current clinical agents was replaced with novel, less avid metal-binding groups in concert with potency-enhancing molecular scaffold modifications. This process produced a unique series of fungal CYP51-selective inhibitors that included the oral antifungal 7d (VT-1161), now in Phase 2 clinical trials. This series exhibits excellent potency against key yeast and dermatophyte strains. The chemical methodology described is potentially applicable to the design of new and more effective metalloenzyme inhibitor treatments for a broad array of diseases. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.05.068

文献信息

• An Enantioselective Synthesis of Voriconazole
  作者：Keiji Tamura、Makoto Furutachi、Naoya Kumagai、Masakatsu Shibasaki

  DOI：10.1021/jo4019528

  日期：2013.11.15

  A new seven-step sequence to access voriconazole, a clinically used antifungal agent, was developed. The initial catalytic asymmetric cyanosilylation is the key to constructing the consecutive tetra- and trisubstituted stereogenic centers. The fluoropyrimidine unit frequently triggered unexpected side reactions, but careful amendment of the reaction sequence allowed for the concise enantioselective synthesis.
• Design and optimization of highly-selective fungal CYP51 inhibitors
  作者：William J. Hoekstra、Edward P. Garvey、William R. Moore、Stephen W. Rafferty、Christopher M. Yates、Robert J. Schotzinger

  DOI：10.1016/j.bmcl.2014.05.068

  日期：2014.8

  While the orally-active azoles such as voriconazole and itraconazole are effective antifungal agents, they potently inhibit a broad range of off-target human cytochrome P450 enzymes (CYPs) leading to various safety issues (e.g., drug-drug interactions, liver toxicity). Herein, we describe rationally-designed, broad-spectrum antifungal agents that are more selective for the target fungal enzyme, CYP51, than related human CYP enzymes such as CYP3A4. Using proprietary methodology, the triazole metal-binding group found in current clinical agents was replaced with novel, less avid metal-binding groups in concert with potency-enhancing molecular scaffold modifications. This process produced a unique series of fungal CYP51-selective inhibitors that included the oral antifungal 7d (VT-1161), now in Phase 2 clinical trials. This series exhibits excellent potency against key yeast and dermatophyte strains. The chemical methodology described is potentially applicable to the design of new and more effective metalloenzyme inhibitor treatments for a broad array of diseases. (C) 2014 Elsevier Ltd. All rights reserved.