Abstract
The design of amide and heteroaryl amide isosteres as replacements for the carbamate substructure in previously disclosed 2,6-disubstituted piperidine N-arylsulfonamides is described. In several cases, amides lessened CYP liabilities in this class of gamma-secretase inhibitors. Selected compounds showed significant reduction of Abeta levels upon oral dosing in a transgenic murine model of Alzheimer's disease.
MeSH terms
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Amides / chemistry*
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Amides / pharmacokinetics
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Amides / pharmacology*
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Amyloid beta-Peptides / metabolism
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Animals
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Carbamates / chemistry
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Carbamates / pharmacokinetics
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Carbamates / pharmacology
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Cytochrome P-450 Enzyme Inhibitors
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Heterocyclic Compounds / chemistry*
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Heterocyclic Compounds / pharmacokinetics
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Heterocyclic Compounds / pharmacology*
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Mice
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Oxadiazoles / chemistry
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Oxadiazoles / pharmacokinetics
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Oxadiazoles / pharmacology
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Piperidines / chemistry
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Piperidines / pharmacokinetics
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Piperidines / pharmacology
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Protease Inhibitors / chemistry*
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Protease Inhibitors / pharmacokinetics
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Protease Inhibitors / pharmacology*
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Rats
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Structure-Activity Relationship
Substances
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Amides
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Amyloid beta-Peptides
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Carbamates
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Cytochrome P-450 Enzyme Inhibitors
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Heterocyclic Compounds
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Oxadiazoles
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Piperidines
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Protease Inhibitors
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Amyloid Precursor Protein Secretases