(2S,3S)-3-amino-1,1,1-trifluoro-3-phenylpropan-2-ol | 213601-53-7

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: (2S,3S)-3-amino-1,1,1-trifluoro-3-phenylpropan-2-ol
• CAS: 213601-53-7
• 化学式: C₉H₁₀F₃NO
• 分子量: 205.18
• InChiKey: GFSZBXASMXIZSV-YUMQZZPRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  14
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  46.2
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (2S,3S)-3-amino-1,1,1-trifluoro-3-phenylpropan-2-ol 、 5-氯-1-甲基-1H-吲哚-2-羧酸 在 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 二甲基亚砜 为溶剂， 反应 1.58h， 以85%的产率得到5-chloro-1-methyl-1H-indole-2-carboxylic acid ((trans)-3,3,3-trifluoro-2-hydroxy-1-phenylpropyl)amide
  参考文献：
  名称：

  Intracellular Trapping of the Selective Phosphoglycerate Dehydrogenase (PHGDH) Inhibitor BI-4924 Disrupts Serine Biosynthesis

  摘要：

  Phosphoglycerate dehydrogenase (PHGDH) is known to be the rate-limiting enzyme in the serine synthesis pathway in humans. It converts glycolysis-derived 3-phosphoglycerate to 3-phosphopyruvate in a co-factor-dependent oxidation reaction. Herein, we report the discovery of BI-4916, a prodrug of the co-factor nicotinamide adenine dinucleotide (NADH/NAD(+))-competitive PHGDH inhibitor BI-4924, which has shown high selectivity against the majority of other dehydrogenase targets. Starting with a fragment-based screening, a subsequent hit optimization using structure-based drug design was conducted to deliver a single-digit nanomolar lead series and to improve potency by 6 orders of magnitude. To this end, an intracellular ester cleavage mechanism of the ester prodrug was utilized to achieve intracellular enrichment of the actual carboxylic acid based drug and thus overcome high cytosolic levels of the competitive cofactors NADH/NAD(+).

  DOI：

  10.1021/acs.jmedchem.9b00718

文献信息

• Synthesis and utilization of trifluoromethylated amino alcohol ligands for the enantioselective Reformatsky reaction and addition of diethylzinc to N-(diphenylphosphinoyl)imine
  作者：Xiu-Hua Xu、Xiao-Long Qiu、Feng-Ling Qing

  DOI：10.1016/j.tet.2008.05.043

  日期：2008.7

  successfully applied in the enantioselective Reformatsky reaction and addition of diethylzinc to N-(diphenylphosphinoyl)imine, respectively. The influence of the substituents on C-3 position and the amino moiety on the enantioselectivity has been carefully investigated. In the best cases, ligand 1b exhibited good selectivity for the enantioselective Reformatsky reaction in 86% ee and ligand 12d provided excellent

  设计并方便地制备了一系列三氟甲基化的氨基醇配体，分别成功地用于对映选择性的Reformatsky反应和将二乙基锌分别添加到N-（二苯基膦酰基）亚胺中。仔细研究了取代基对C-3位和氨基部分对映选择性的影响。在最佳情况下，配体1b对86％ee的对映选择性Reformatsky反应表现出良好的选择性，而配体12d通过向具有95％ee的N-（二苯基膦酰基）亚胺中添加二乙基锌，提供了出色的对映选择性。
• Intracellular Trapping of the Selective Phosphoglycerate Dehydrogenase (PHGDH) Inhibitor <b>BI-4924</b> Disrupts Serine Biosynthesis
  作者：Harald Weinstabl、Matthias Treu、Joerg Rinnenthal、Stephan K. Zahn、Peter Ettmayer、Gerd Bader、Georg Dahmann、Dirk Kessler、Klaus Rumpel、Nikolai Mischerikow、Fabio Savarese、Thomas Gerstberger、Moriz Mayer、Andreas Zoephel、Renate Schnitzer、Wolfgang Sommergruber、Paola Martinelli、Heribert Arnhof、Biljana Peric-Simov、Karin S. Hofbauer、Géraldine Garavel、Yvonne Scherbantin、Sophie Mitzner、Thomas N. Fett、Guido Scholz、Jens Bruchhaus、Michelle Burkard、Roland Kousek、Tuncay Ciftci、Bernadette Sharps、Andreas Schrenk、Christoph Harrer、Daniela Haering、Bernhard Wolkerstorfer、Xuechun Zhang、Xiaobing Lv、Alicia Du、Dongyang Li、Yali Li、Jens Quant、Mark Pearson、Darryl B. McConnell

  DOI：10.1021/acs.jmedchem.9b00718

  日期：2019.9.12

  Phosphoglycerate dehydrogenase (PHGDH) is known to be the rate-limiting enzyme in the serine synthesis pathway in humans. It converts glycolysis-derived 3-phosphoglycerate to 3-phosphopyruvate in a co-factor-dependent oxidation reaction. Herein, we report the discovery of BI-4916, a prodrug of the co-factor nicotinamide adenine dinucleotide (NADH/NAD(+))-competitive PHGDH inhibitor BI-4924, which has shown high selectivity against the majority of other dehydrogenase targets. Starting with a fragment-based screening, a subsequent hit optimization using structure-based drug design was conducted to deliver a single-digit nanomolar lead series and to improve potency by 6 orders of magnitude. To this end, an intracellular ester cleavage mechanism of the ester prodrug was utilized to achieve intracellular enrichment of the actual carboxylic acid based drug and thus overcome high cytosolic levels of the competitive cofactors NADH/NAD(+).