Abstract
Cyclic hydroxyamidines were designed and validated as isosteric replacements of the amide functionality. Compounds with these structural motifs were found to be metabolically stable and to possess highly desirable pharmacokinetic profiles. These designs were applied in the identification of γ-secretase modulators leading to highly efficacious agents for reduction of central nervous system Aβ(42) in various animal models.
MeSH terms
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Amidines / chemical synthesis*
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Amidines / pharmacokinetics
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Amidines / pharmacology
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Amyloid Precursor Protein Secretases / metabolism*
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Amyloid beta-Peptides / metabolism
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Animals
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Brain / metabolism
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Dogs
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HEK293 Cells
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Humans
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Macaca fascicularis
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Male
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Oxadiazoles / chemical synthesis*
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Oxadiazoles / pharmacokinetics
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Oxadiazoles / pharmacology
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Oxazines / chemical synthesis*
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Oxazines / pharmacokinetics
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Oxazines / pharmacology
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Peptide Fragments / metabolism
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Rats
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Amidines
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Amyloid beta-Peptides
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Oxadiazoles
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Oxazines
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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