Abstract
The design and the synthesis of several chemical subclasses of imidazole containing γ-secretase modulators (GSMs) is described. Conformational restriction of pyridone 4 into bicyclic pyridone isosteres has led to compounds with high in vitro and in vivo potency. This has resulted in the identification of benzimidazole 44a as a GSM with low nanomolar potency in vitro. In mouse, rat, and dog, this compound displayed the typical γ-secretase modulatory profile by lowering Aβ42 and Aβ40 levels combined with an especially pronounced increase in Aβ38 and Aβ37 levels while leaving the total levels of amyloid peptides unchanged.
MeSH terms
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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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Benzimidazoles / chemical synthesis*
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Benzimidazoles / pharmacokinetics
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Benzimidazoles / pharmacology
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Benzoxazoles / chemical synthesis
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Benzoxazoles / pharmacokinetics
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Benzoxazoles / pharmacology
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Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
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Bridged Bicyclo Compounds, Heterocyclic / pharmacokinetics
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology
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Cell Line, Tumor
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Dogs
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Drug Design
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Humans
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Imidazoles / chemical synthesis*
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Imidazoles / pharmacokinetics
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Imidazoles / pharmacology
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Indazoles / chemical synthesis
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Indazoles / pharmacokinetics
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Indazoles / pharmacology
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Male
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Mice
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Microsomes, Liver / metabolism
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Molecular Conformation
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Peptide Fragments / metabolism
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Pyridines / chemical synthesis
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Pyridines / pharmacokinetics
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Pyridines / pharmacology
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Rats
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Rats, Sprague-Dawley
Substances
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(2-(4-fluoro-phenyl)-1-methyl-1H-benzoimidazol-4-yl)-(6-methoxy-5-(4-methyl-imidazol-1-yl)-pyridin-2-yl)-amine
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Amyloid beta-Peptides
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Benzimidazoles
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Benzoxazoles
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Bridged Bicyclo Compounds, Heterocyclic
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Imidazoles
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Indazoles
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Peptide Fragments
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Pyridines
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amyloid beta-protein (1-38)
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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