Highly potent macrocyclic BACE-1 inhibitors incorporating a hydroxyethylamine core: Design, synthesis and X-ray crystal structures of enzyme inhibitor complexes
| Autor: | Jimmy Lindberg, Veronica Sandgren, Per-Ola Johansson, Bertil Samuelsson, Tatiana Agback, Oscar Belda, Anders Dahlgren, Ingemar Kvarnström |
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| Rok vydání: | 2012 |
| Předmět: |
Isostere
Stereochemistry Clinical Biochemistry Substituent Pharmaceutical Science Crystallography X-Ray Ring (chemistry) Biochemistry Structure-Activity Relationship chemistry.chemical_compound Naturvetenskap Drug Discovery Ethylamines Moiety Structure–activity relationship Enzyme Inhibitors Binding site Molecular Biology Alzheimer’s disease BACE-1 inhibition Macrocycles Hydroxyethylamine (HEA) isostere chemistry.chemical_classification Binding Sites biology Organic Chemistry Protein Structure Tertiary Enzyme chemistry Enzyme inhibitor Drug Design biology.protein Molecular Medicine Amyloid Precursor Protein Secretases Natural Sciences |
| Zdroj: | Bioorganic & Medicinal Chemistry. 20:4377-4389 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2012.05.039 |
| Popis: | A series of P1-P3 linked macrocyclic BACE-1 inhibitors containing a hydroxyethylamine (HEA) isostere scaffold has been synthesized. All inhibitors comprise a toluene or N-phenylmethanesulfonamide P2 moiety. Excellent BACE-1 potencies, both in enzymatic and cell-based assays, were observed in this series of target compounds, with the best candidates displaying cell-based IC50 values in the low nanomolar range. As an attempt to improve potency, a phenyl substituent aiming at the S3 subpocket was introduced in the macrocyclic ring. X-ray analyses were performed on selected compounds, and enzyme-inhibitor interactions are discussed. On the day of the defence day the status of this article was Manuscript. |
| Databáze: | OpenAIRE |
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