2-methyl-5-phenyl-2H-pyrazole-3-carboxylic acid [1-(4-acetylsulfamoylphenyl)ethyl]amide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 2-methyl-5-phenyl-2H-pyrazole-3-carboxylic acid [1-(4-acetylsulfamoylphenyl)ethyl]amide
• 英文别名: N-[1-[4-(acetylsulfamoyl)phenyl]ethyl]-2-methyl-5-phenylpyrazole-3-carboxamide
• 化学式: C₂₁H₂₂N₄O₄S
• 分子量: 426.496
• InChiKey: ALORMMGXOAQIFS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  119
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  2-甲基-5-苯基-2H-吡唑-3-甲酸 、 4-(1-氨基-乙基)-苯磺酸酰胺 在 三乙胺 、 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 二氯甲烷 、 二甲基亚砜 为溶剂， 反应 34.58h， 生成 2-methyl-5-phenyl-2H-pyrazole-3-carboxylic acid [1-(4-acetylsulfamoylphenyl)ethyl]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

• 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(+).