Design and synthesis of pyridine–pyrazolopyridine-based inhibitors of protein kinase B/Akt
| Autor: | Qun Li, Eric F. Johnson, Viraj B. Gandhi, Ran Guan, Saul H. Rosenberg, Jianchun Gong, Vincent S. Stoll, Keith W. Woods, Yan Luo, Vered Klinghofer, Xuesong Liu, Gui-Dong Zhu, Vincent L. Giranda, Mulugeta Mamo |
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| Rok vydání: | 2007 |
| Předmět: |
Pyridines
Stereochemistry Clinical Biochemistry Pharmaceutical Science Crystallography X-Ray Biochemistry Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Pyrazolopyridine Tumor Cells Cultured Humans Structure–activity relationship Enzyme Inhibitors Protein kinase A Protein Kinase Inhibitors Molecular Biology Protein kinase B Serine/threonine-specific protein kinase Indazole biology Organic Chemistry Pancreatic Neoplasms chemistry Protein kinase domain Enzyme inhibitor biology.protein Pyrazoles Molecular Medicine Proto-Oncogene Proteins c-akt |
| Zdroj: | Bioorganic & Medicinal Chemistry. 15:2441-2452 |
| ISSN: | 0968-0896 |
| Popis: | Thr-211 is one of three different amino acid residues in the kinase domain of protein kinase B/Akt as compared to protein kinase A (PKA), a closely related analog in the same AGC family. In an attempt to improve the potency and selectivity of our indazole-pyridine series of Akt inhibitors over PKA, efforts have focused on the incorporation of a chemical functionality to interact with the hydroxy group of Thr-211. Several substituents including an oxygen anion, amino, and nitro groups have been introduced at the C-6 position of the indazole scaffold, leading to a significant drop in Akt potency. Incorporation of a nitrogen atom into the phenyl ring at the same position (i.e., 9f) maintained the Akt activity and, in some cases, improved the selectivity over PKA. The structure-activity relationships of the new pyridine-pyrazolopyridine series of Akt inhibitors and their structural features when bound to PKA are also discussed. |
| Databáze: | OpenAIRE |
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