Abstract
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.
MeSH terms
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Amyloid Precursor Protein Secretases / chemistry
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Amyloid beta-Peptides / blood
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Amyloid beta-Peptides / cerebrospinal fluid
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Amyloid beta-Peptides / metabolism*
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Animals
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Aspartic Acid Endopeptidases / antagonists & inhibitors*
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Aspartic Acid Endopeptidases / chemistry
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Brain / drug effects*
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Brain / metabolism
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Cell Line
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Crystallography, X-Ray
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Dogs
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Female
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Guinea Pigs
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Humans
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Imidazoles / chemical synthesis*
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Imidazoles / chemistry
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Imidazoles / pharmacology
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Male
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Mice
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Mice, Inbred C57BL
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Models, Molecular
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Molecular Structure
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Peptide Fragments / blood
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Peptide Fragments / cerebrospinal fluid
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Peptide Fragments / metabolism*
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Permeability
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Stereoisomerism
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Structure-Activity Relationship
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Tissue Distribution
Substances
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Amyloid beta-Peptides
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Imidazoles
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Peptide Fragments
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amyloid beta-protein (1-40)
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amyloid beta-protein (1-42)
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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BACE1 protein, human