Pyrazolopyridine inhibitors of B-RafV600E. Part 2: structure-activity relationships
| Autor: | Jonas Grina, David A. Moreno, Alexandre J. Buckmelter, Ellen R. Laird, Steve Wenglowsky, Li Ren, Jeongbeob Seo, Bainian Feng, Simon Mathieu, Stefan Gradl, Joachim Rudolph, Susan L. Gloor, Paul Lunghofer, Brad Newhouse, Walter C. Voegtli, Kateri A. Ahrendt, Joshua D. Hansen, Tyler Risom, Zhaoyang Wen, Hillary L. Sturgis |
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| Rok vydání: | 2011 |
| Předmět: |
Models
Molecular Proto-Oncogene Proteins B-raf Stereochemistry Pyridines Clinical Biochemistry Pharmaceutical Science Crystallography X-Ray Biochemistry chemistry.chemical_compound Structure-Activity Relationship Drug Discovery Pyrazolopyridine Structure–activity relationship Molecular Biology Protein Kinase Inhibitors chemistry.chemical_classification Dose-Response Relationship Drug Molecular Structure Aryl Organic Chemistry Stereoisomerism Sulfonamide Enzyme chemistry Molecular Medicine Pyrazoles |
| Zdroj: | Bioorganicmedicinal chemistry letters. 21(18) |
| ISSN: | 1464-3405 |
| Popis: | Structure–activity relationships around a novel series of B-RafV600E inhibitors are reported. The enzymatic and cellular potencies of inhibitors derived from two related hinge-binding groups were compared and3-methoxypyrazolopyridine proved to be superior. The 3-alkoxy group of lead B-RafV600E inhibitor 1 was extended and minimally affected potency. The propyl sulfonamide tail of compound 1, which occupies the small lipophilic pocket formed by an outward shift of the αC-helix, was expanded to a series of arylsulfonamides. X-ray crystallography revealed that this lipophilic pocket unexpectedly enlarges to accommodate the bulkier aryl group. |
| Databáze: | OpenAIRE |
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