Document Detail

New aminoimidazoles as β-secretase (BACE-1) inhibitors showing amyloid-β (Aβ) lowering in brain.
MedLine Citation:
PMID:  23017051     Owner:  NLM     Status:  MEDLINE    
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.
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:
Type:  Journal Article     Date:  2012-10-03
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  55     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-08     Completed Date:  2013-02-26     Revised Date:  2013-03-06    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  9297-311     Citation Subset:  IM    
Department of Medicinal Chemistry, AstraZeneca R&D Södertälje, SE-151 85 Södertälje, Sweden.
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MeSH Terms
Amyloid Precursor Protein Secretases / antagonists & inhibitors*,  chemistry
Amyloid beta-Peptides / blood,  cerebrospinal fluid,  metabolism*
Aspartic Acid Endopeptidases / antagonists & inhibitors*,  chemistry
Brain / drug effects*,  metabolism
Cell Line
Crystallography, X-Ray
Guinea Pigs
Imidazoles / chemical synthesis*,  chemistry,  pharmacology
Mice, Inbred C57BL
Models, Molecular
Molecular Structure
Peptide Fragments / blood,  cerebrospinal fluid,  metabolism*
Structure-Activity Relationship
Tissue Distribution
Reg. No./Substance:
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 protein, human
Erratum In:
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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