Fragment-based discovery of potent ERK2 pyrrolopyrazine inhibitors
| Autor: | Daniel J. Burdick, Lauren Goeser, Jianping Yin, Shumei Wang, John Moffat, Steven Magnuson, Weiru Wang, Jeff Blaney, Huifen Chen, Borlan Pan, Christopher E. Heise, Jake Drummond |
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| Rok vydání: | 2015 |
| Předmět: |
Models
Molecular Pyrazine Stereochemistry Clinical Biochemistry Pharmaceutical Science Crystal structure Biochemistry Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Humans Imidazole Molecule Structure–activity relationship Pyrroles Molecular Biology Mitogen-Activated Protein Kinase 1 Dose-Response Relationship Drug Molecular Structure Chemistry Fragment (computer graphics) Drug discovery Organic Chemistry Combinatorial chemistry Pyrazines Molecular Medicine |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 25:4728-4732 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2015.08.048 |
| Popis: | A fragment-based lead discovery approach was used to discover novel ERK2 inhibitors. The crystal structure of N-benzyl-9H-purin-6-amine 1 in complex with ERK2 elucidated its hinge-binding mode. In addition, the simultaneous binding of an imidazole molecule adjacent to 1 suggested a direction for fragment expansion. Structure-based core hopping applied to 1 led to 5H-pyrrolo[3,2-b]pyrazine (3) that afforded direct vectors to probe the pockets of interest while retaining the essential hinge binding elements. Utilizing the new vectors for SAR exploration, the new core 3 was quickly optimized to compound 39 resulting in a greater than 6600-fold improvement in potency. |
| Databáze: | OpenAIRE |
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