1-(3,4-dichlorophenyl)pyrrolidine-3-carboxylic acid

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: 1-(3,4-dichlorophenyl)pyrrolidine-3-carboxylic acid
• 英文别名: 1-(3,4-Dichlorophenyl)pyrrolidine-3-carboxylic acid
• 化学式: C₁₁H₁₁Cl₂NO₂
• 分子量: 260.12
• InChiKey: YFQDFLNYWPENSQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  40.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  在 水 、 sodium hydroxide 作用下， 以 甲醇 为溶剂， 反应 2.0h， 以70.8 mg的产率得到1-(3,4-dichlorophenyl)pyrrolidine-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

• [EN] N-(1-HYDROXY-3-(PYRROLIDINYL)PROPAN-2-YL)PYRROLIDINE-3-CARBOXAMIDE DERIVATIVES AS GLUCOSYLCERAMIDE SYNTHASE INHIBITORS<br/>[FR] DÉRIVÉS N-(1-HYDROXY-3-(PYRROLIDINYL)PROPAN-2-YL)PYRROLIDINE-3-CARBOXAMIDE UTILES EN TANT QU'INHIBITEURS DE LA GLUCOSYLCÉRAMIDE SYNTHASE
  申请人：BIOMARIN PHARM INC

  公开号：WO2015065937A1

  公开（公告）日：2015-05-07

  Described herein are compounds of Formula I, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and compounds I for use to treat or prevent diseases or conditions associated with the enzyme glucosylceramide synthase (GCS).

  本处描述的是公式I的化合物，制造此类化合物的方法，包含此类化合物的药物组合物和药品，以及用于治疗或预防与葡萄糖苷鞘氨醇合酶（GCS）相关疾病的I化合物。
• N-(1-hydroxy-3-(pyrrolidinyl)propan-2-yl)pyrrolidine-3-carboxamide derivatives as glucosylceramide synthase inhibitors
  申请人：BIOMARIN PHARMACEUTICAL INC.

  公开号：US10239832B2

  公开（公告）日：2019-03-26

  Described herein are compounds of Formula I, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and compounds I for use to treat or prevent diseases or conditions associated with the enzyme glucosylceramide synthase (GCS).

  本文描述了式 I 化合物、制造此类化合物的方法、含有此类化合物的药物组合物和药物，以及用于治疗或预防与葡萄糖酰胺合成酶 (GCS) 相关的疾病或病症的式 I 化合物。
• N-(1-HYDROXY-3-(PYRROLIDINYL)PROPAN-2-YL)PYRROLIDINE-3-CARBOXAMIDE DERIVATIVES AS GLUCOSYLCERAMIDE SYNTHASE INHIBITORS
  申请人：BioMarin Pharmaceutical Inc.

  公开号：EP3063141B1

  公开（公告）日：2018-02-28
• 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.