| New aminoimidazoles as β-secretase (BACE-1) inhibitors showing amyloid-β (Aβ) lowering in brain. | |
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MedLine Citation:
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PMID: 23017051 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Amino-2H-imidazoles are described as a new class of BACE-1 inhibitors for the treatment of Alzheimer's disease. Synthetic methods, crystal structures, and structure-activity relationships for target activity, permeability, and hERG activity are reported and discussed. Compound (S)-1m was one of the most promising compounds in this report, with high potency in the cellular assay and a good overall profile. When guinea pigs were treated with compound (S)-1m, a concentration and time dependent decrease in Aβ40 and Aβ42 levels in plasma, brain, and CSF was observed. The maximum reduction of brain Aβ was 40-50%, 1.5 h after oral dosing (100 μmol/kg). The results presented highlight the potential of this new class of BACE-1 inhibitors with good target potency and with low effect on hERG, in combination with a fair CNS exposure in vivo. |
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Authors:
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Ylva Gravenfors; Jenny Viklund; Jan Blid; Tobias Ginman; Sofia Karlström; Jacob Kihlström; Karin Kolmodin; Johan Lindström; Stefan von Berg; Fredrik von Kieseritzky; Krisztian Bogar; Can Slivo; Britt-Marie Swahn; Lise-Lotte Olsson; Patrik Johansson; Susanna Eketjäll; Johanna Fälting; Fredrik Jeppsson; Kia Strömberg; Juliette Janson; Fredrik Rahm |
Publication Detail:
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Type: Journal Article Date: 2012-10-03 |
Journal Detail:
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Title: Journal of medicinal chemistry Volume: 55 ISSN: 1520-4804 ISO Abbreviation: J. Med. Chem. Publication Date: 2012 Nov |
Date Detail:
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Created Date: 2012-11-08 Completed Date: 2013-02-26 Revised Date: 2013-03-06 |
Medline Journal Info:
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Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: United States |
Other Details:
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Languages: eng Pagination: 9297-311 Citation Subset: IM |
Affiliation:
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Department of Medicinal Chemistry, AstraZeneca R&D Södertälje, SE-151 85 Södertälje, Sweden. ylva.gravenfors@hotmail.com |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amyloid Precursor Protein Secretases
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antagonists & inhibitors*,
chemistry Amyloid beta-Peptides / blood, cerebrospinal fluid, metabolism* Animals Aspartic Acid Endopeptidases / antagonists & inhibitors*, chemistry Brain / drug effects*, metabolism Cell Line Crystallography, X-Ray Dogs Female Guinea Pigs Humans Imidazoles / chemical synthesis*, chemistry, pharmacology Male Mice Mice, Inbred C57BL Models, Molecular Molecular Structure Peptide Fragments / blood, cerebrospinal fluid, metabolism* Permeability Stereoisomerism Structure-Activity Relationship Tissue Distribution |
| Chemical | |
Reg. No./Substance:
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0/Amyloid beta-Peptides; 0/Imidazoles; 0/Peptide Fragments; 0/amyloid beta-protein (1-40); 0/amyloid beta-protein (1-42); EC 3.4.-/Amyloid Precursor Protein Secretases; EC 3.4.23.-/Aspartic Acid Endopeptidases; EC 3.4.23.46/BACE1 protein, human |
| Comments/Corrections | |
Erratum In:
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J Med Chem. 2012 Nov 26;55(22):10316 Note: Bogar, Krisztian [added] |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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