Synthesis of potent BACE-1 inhibitors incorporating a hydroxyethylene isostere as central core
| Autor: | Karin Gustafsson, Jimmy Lindberg, Ingemar Kvarnström, Bertil Samuelsson, Fredrik Wångsell, Anders Hallberg, Åsa Rosenquist, Katarina Jansson, Neera Borkakoti, Michael Edlund |
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| Rok vydání: | 2010 |
| Předmět: |
Molecular model
medicine.drug_class Isostere Stereochemistry Substituent Carboxamide Crystallography X-Ray Chemical synthesis Cell Line Inhibitory Concentration 50 Structure-Activity Relationship chemistry.chemical_compound Drug Discovery medicine Aspartic Acid Endopeptidases Humans Enzyme Inhibitors Pharmacology chemistry.chemical_classification Molecular Structure biology Organic Chemistry Stereoisomerism General Medicine Ethylenes Sulfonamide chemistry Enzyme inhibitor Drug Design biology.protein Amyloid Precursor Protein Secretases Lactone |
| Zdroj: | European Journal of Medicinal Chemistry. 45:870-882 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2009.11.013 |
| Popis: | We herein describe the design and synthesis of a series of BACE-1 inhibitors incorporating a P1-substituted hydroxylethylene transition state isostere. The synthetic route starting from commercially available carbohydrates yielded a pivotal lactone intermediate with excellent stereochemical control which subsequently could be diversified at the P1-position. The final inhibitors were optimized using three different amines to provide the residues in the P2'-P3' position and three different acids affording the residues in the P2-P3 position. In addition we report on the stereochemical preference of the P1'-methyl substituent in the synthesized inhibitors. All inhibitors were evaluated in an in vitro BACE-1 assay where the most potent inhibitor, 34-(R), exhibited a BACE-1 IC(50) value of 3.1 nM. |
| Databáze: | OpenAIRE |
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