Synthesis and structure-activity relationships of (aryloxy)quinazoline ureas as novel, potent, and selective vascular endothelial growth factor receptor-2 inhibitors
| Autor: | Laurence Goossens, Perrine Six, Amaury Farce, Amélie Lemoine, Patrick Depreux, Antonio Garofalo, Séverine Ravez, Philippe Chavatte |
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| Rok vydání: | 2012 |
| Předmět: |
chemistry.chemical_classification
Models Molecular Chemistry Kinase Stereochemistry Quantitative Structure-Activity Relationship Kinase insert domain receptor Antineoplastic Agents Vascular Endothelial Growth Factor Receptor-2 chemistry.chemical_compound Enzyme Growth factor receptor Biochemistry Docking (molecular) Catalytic Domain Cell Line Tumor Drug Discovery Quinazoline Quinazolines Molecular Medicine Humans Urea Drug Screening Assays Antitumor Receptor Tyrosine kinase |
| Zdroj: | Journal of medicinal chemistry. 55(3) |
| ISSN: | 1520-4804 |
| Popis: | In our continuing search for medicinal agents to treat proliferative diseases, quinazoline derivatives were synthesized and evaluated pharmacologically as epithelial growth factor receptor and vascular endothelial growth factor receptor 2 (VEGFR-2) tyrosine kinase inhibitors. A quantitative structure-activity relationship analysis was conducted to rationalize the structure-activity relationship and to predict how similar the inhibitor-binding profiles of two protein kinases are likely to be on the basis of the docking of lead coumpounds into the ATP-binding site. This model was used to direct the synthesis of new compounds. A series of N-(aromatic)-N'-{4-[(6,7-dimethoxyquinazolin-4-yl)oxy]phenyl}urea were identified as potent and selective inhibitors of the tyrosine kinase activity of VEGFR-2 (fetal liver kinase 1, kinase insert domain-containing receptor). An efficient route was developed that enabled the synthesis of a wide variety of analogues with substitution on several positions of the template. Substitution of diarylurea, competitive with ATP, afforded several analogues with low nanomolar inhibition of enzymatic activity of VEGFR-2. In this paper, we describe the synthesis, structure-activity relationships, and pharmacological characterization of the series. |
| Databáze: | OpenAIRE |
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