1-(2-benzyl-3-oxoisoindoline-4-carbonyl)pyrrolidine-2-carbonitrile | 1390623-33-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 英文名称: 1-(2-benzyl-3-oxoisoindoline-4-carbonyl)pyrrolidine-2-carbonitrile
• 英文别名: (S)-1-(2-benzyl-3-oxoisoindoline-4-carbonyl)pyrrolidine-2-carbonitrile；(2S)-1-(2-benzyl-3-oxo-1H-isoindole-4-carbonyl)pyrrolidine-2-carbonitrile
• CAS: 1390623-33-2
• 化学式: C₂₁H₁₉N₃O₂
• 分子量: 345.401
• InChiKey: AUHQVJXPKRFCST-KRWDZBQOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  26
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  64.4
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  2-benzyl-1-oxo-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole-7-carboxylic acid 在 盐酸 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 三乙胺 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 生成 1-(2-benzyl-3-oxoisoindoline-4-carbonyl)pyrrolidine-2-carbonitrile
  参考文献：
  名称：

  Virtual Screening and Computational Optimization for the Discovery of Covalent Prolyl Oligopeptidase Inhibitors with Activity in Human Cells

  摘要：

  Our docking program, Fitted, implemented in our computational platform, Forecaster, has been modified to carry out automated virtual screening of covalent inhibitors. With this modified version of the program, virtual screening and further docking-based optimization of a selected hit led to the identification of potential covalent reversible inhibitors of prolyl oligopeptidase activity. After visual inspection, a virtual hit molecule together with four analogues were selected for synthesis and made in one five chemical steps. Biological evaluations on recombinant POP and FAP alpha enzymes, cell extracts, and living cells demonstrated high potency and selectivity for POP over FAP alpha and DPPIV. Three compounds even exhibited high nanomolar inhibitory activities in intact living human cells and acceptable metabolic stability. This small set of molecules also demonstrated that covalent binding and/or geometrical constraints to the ligand/protein complex may lead to an increase in bioactivity.

  DOI：

  10.1021/jm3002839

文献信息

• Virtual Screening and Computational Optimization for the Discovery of Covalent Prolyl Oligopeptidase Inhibitors with Activity in Human Cells
  作者：Stéphane De Cesco、Sébastien Deslandes、Eric Therrien、David Levan、Mickaël Cueto、Ralf Schmidt、Louis-David Cantin、Anthony Mittermaier、Lucienne Juillerat-Jeanneret、Nicolas Moitessier

  DOI：10.1021/jm3002839

  日期：2012.7.26

  Our docking program, Fitted, implemented in our computational platform, Forecaster, has been modified to carry out automated virtual screening of covalent inhibitors. With this modified version of the program, virtual screening and further docking-based optimization of a selected hit led to the identification of potential covalent reversible inhibitors of prolyl oligopeptidase activity. After visual inspection, a virtual hit molecule together with four analogues were selected for synthesis and made in one five chemical steps. Biological evaluations on recombinant POP and FAP alpha enzymes, cell extracts, and living cells demonstrated high potency and selectivity for POP over FAP alpha and DPPIV. Three compounds even exhibited high nanomolar inhibitory activities in intact living human cells and acceptable metabolic stability. This small set of molecules also demonstrated that covalent binding and/or geometrical constraints to the ligand/protein complex may lead to an increase in bioactivity.
• Integrated Synthetic, Biophysical, and Computational Investigations of Covalent Inhibitors of Prolyl Oligopeptidase and Fibroblast Activation Protein α
  作者：Jessica Plescia、Stéphane De Cesco、Mihai Burai Patrascu、Jerry Kurian、Justin Di Trani、Caroline Dufresne、Alexander S. Wahba、Naëla Janmamode、Anthony K. Mittermaier、Nicolas Moitessier

  DOI：10.1021/acs.jmedchem.9b00642

  日期：2019.9.12

  Over the past decade, there has been increasing interest in covalent inhibition as a drug design strategy. Our own interest in the development of prolyl oligopeptidase (POP) and fibroblast activation protein alpha (FAP) covalent inhibitors has led us to question whether these two serine proteases were equal in terms of their reactivity toward electrophilic warheads. To streamline such investigations, we exploited both computational and experimental methods to investigate the influence of different reactive groups on both potency and binding kinetics using both our own series of POP inhibitors and others' discovered hits. A direct correlation between inhibitor reactivity and residence time was demonstrated through quantum mechanics methods and further supported by experimental studies. This computational method was also successfully applied to FAP, as an overview of known FAP inhibitors confirmed our computational predictions that more reactive warheads (e.g., boronic acids) must be employed to inhibit FAP than for POP.