The identification of 8,9-dimethoxy-5-(2-aminoalkoxy-pyridin-3-yl)-benzo[c][2,7]naphthyridin-4-ylamines as potent inhibitors of 3-phosphoinositide-dependent kinase-1 (PDK-1)
| Autor: | Xin Han, Charles Ingalls, Russell Dushin, Middleton Brawner Floyd, Thomas Nittoli, Katherine Cheung, Yongbo Hu, K T Arndt, G. Grosu, Bing Guo, Heidi L. Fraser, Allan Wissner, Andrea Olland |
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| Rok vydání: | 2010 |
| Předmět: |
Models
Molecular Pyridines Stereochemistry Static Electricity Protein Serine-Threonine Kinases Crystallography X-Ray 3-Phosphoinositide-Dependent Protein Kinases Structure-Activity Relationship Drug Discovery Structure–activity relationship Protein Kinase Inhibitors Pharmacology chemistry.chemical_classification Protein-Serine-Threonine Kinases Molecular Structure biology Chemistry Kinase Organic Chemistry Active site Hydrogen Bonding General Medicine Enzyme Enzyme inhibitor biology.protein Enantiomer Phosphoinositide-dependent kinase-1 |
| Zdroj: | European Journal of Medicinal Chemistry. 45:1379-1386 |
| ISSN: | 0223-5234 |
| Popis: | A series of 8,9-dimethoxy-5-(2-aminoalkoxy-pyridin-3-yl)-benzo[c][2,7]naphthyridin-4-ylamine-based inhibitors of 3-phosphoinositide-dependent kinase-1 (PDK-1) has been identified. Several examples appear to be potent and relatively selective inhibitors of PDK-1 over the related AGC kinases PKA, PKB/AKT, and p70S6K. The introduction of a stereochemical center beside the amino substituent on the aminoalkoxy-side chain had little effect upon the inhibitory activity against these enzymes, and X-ray crystallographic analyses of a representative pair of enantiomeric inhibitors bound to the active site of PDK-1 revealed comparable binding modes for each enantiomer. |
| Databáze: | OpenAIRE |
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