Substituted 2-oxo-azepane derivatives are potent, orally active γ-secretase inhibitors
| Autor: | Alexander Flohr, Pascale David-Pierson, Eric A. Kitas, Wolfgang Wostl, Harald Mauser, André Alker, Guido Galley, Dieter P. Reinhardt, Helmut Jacobsen, Laurence Ozmen, Roland Jakob-Roetne, Christian Czech |
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| Rok vydání: | 2008 |
| Předmět: |
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Molecular Stereochemistry Clinical Biochemistry Pharmaceutical Science Mice Transgenic Hydroxamic Acids Biochemistry Mice Structure-Activity Relationship chemistry.chemical_compound Azepane Drug Discovery Amyloid precursor protein Animals Humans Protease Inhibitors Molecular Biology ADME chemistry.chemical_classification Hydroxamic acid biology Geminal Organic Chemistry Proteolytic enzymes Azepines Enzyme chemistry biology.protein Lactam Molecular Medicine Amyloid Precursor Protein Secretases |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 18:304-308 |
| ISSN: | 0960-894X |
| Popis: | A hydroxamic acid screening hit 1 was elaborated to 5,5-dimethyl-2-oxoazepane derivatives exhibiting low nanomolar inhibition of γ-secretase, a key proteolytic enzyme involved in Alzheimer’s disease. Early ADME data showed a high metabolic clearance for the geminal dimethyl analogs which could be overcome by replacement with the bioisosteric geminal difluoro group. Synthesis and structure–activity relationship are discussed and in vivo active compounds are presented. |
| Databáze: | OpenAIRE |
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