1-(3,5-dichlorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylic acid

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: 1-(3,5-dichlorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylic acid
• 英文别名: 1-(3,5-Dichlorophenyl)-2,5-dimethylpyrrole-3-carboxylic acid
• 化学式: C₁₃H₁₁Cl₂NO₂
• mdl: MFCD00177054
• 分子量: 284.142
• InChiKey: OXJNJCIZJGRXCX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.153
• 拓扑面积：
  42.2
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为产物：
  描述：

  tert-butyl 2-acetyl-4-oxopentanoate 、 3,5-二氯苯胺 在 水 、 对甲苯磺酸 作用下， 以 乙醇 为溶剂， 反应 24.0h， 以52%的产率得到1-(3,5-dichlorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylic acid
  参考文献：
  名称：

  Screening of a Custom-Designed Acid Fragment Library Identifies 1-Phenylpyrroles and 1-Phenylpyrrolidines as Inhibitors of Notum Carboxylesterase Activity

  摘要：

  The Wnt family of proteins are secreted signaling proteins that play key roles in regulating cellular functions. Recently, carboxylesterase Notum was shown to act as a negative regulator of Wnt signaling by mediating the removal of an essential palmitoleate. Here we disclose two new chemical scaffolds that inhibit Notum enzymatic activity. Our approach was to create a fragment library of 250 acids for screening against Notum in a biochemical assay followed by structure determination by X-ray crystallography. Twenty fragments were identified as hits for Notum inhibition, and 14 of these fragments were shown to bind in the palmitoleate pocket of Notum. Optimization of 1-phenylpyrrole 20, guided by structure-based drug design, identified 20z as the most potent compound from this series. Similarly, the optimization of 1-phenylpyrrolidine 8 gave acid 26. This work demonstrates that inhibition of Notum activity can be achieved by small, drug-like molecules possessing favorable in vitro ADME profiles.

  DOI：

  10.1021/acs.jmedchem.0c00660

文献信息

• Screening of a Custom-Designed Acid Fragment Library Identifies 1-Phenylpyrroles and 1-Phenylpyrrolidines as Inhibitors of Notum Carboxylesterase Activity
  作者：William Mahy、Mikesh Patel、David Steadman、Hannah L. Woodward、Benjamin N. Atkinson、Fredrik Svensson、Nicky J. Willis、Alister Flint、Dimitra Papatheodorou、Yuguang Zhao、Luca Vecchia、Reinis R. Ruza、James Hillier、Sarah Frew、Amy Monaghan、Artur Costa、Magda Bictash、Magnus W. Walter、E. Yvonne Jones、Paul V. Fish

  DOI：10.1021/acs.jmedchem.0c00660

  日期：2020.9.10

  The Wnt family of proteins are secreted signaling proteins that play key roles in regulating cellular functions. Recently, carboxylesterase Notum was shown to act as a negative regulator of Wnt signaling by mediating the removal of an essential palmitoleate. Here we disclose two new chemical scaffolds that inhibit Notum enzymatic activity. Our approach was to create a fragment library of 250 acids for screening against Notum in a biochemical assay followed by structure determination by X-ray crystallography. Twenty fragments were identified as hits for Notum inhibition, and 14 of these fragments were shown to bind in the palmitoleate pocket of Notum. Optimization of 1-phenylpyrrole 20, guided by structure-based drug design, identified 20z as the most potent compound from this series. Similarly, the optimization of 1-phenylpyrrolidine 8 gave acid 26. This work demonstrates that inhibition of Notum activity can be achieved by small, drug-like molecules possessing favorable in vitro ADME profiles.