Abstract
A hydroxamic acid screening hit 1 was elaborated to 5,5-dimethyl-2-oxoazepane derivatives exhibiting low nanomolar inhibition of gamma-secretase, a key proteolytic enzyme involved in Alzheimer's disease. Early ADME data showed a high metabolic clearance for the geminal dimethyl analogs which could be overcome by replacement with the bioisosteric geminal difluoro group. Synthesis and structure-activity relationship are discussed and in vivo active compounds are presented.
MeSH terms
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Animals
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Azepines / chemical synthesis
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Azepines / chemistry*
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Azepines / pharmacology*
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Humans
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Hydroxamic Acids / chemistry
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Mice
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Mice, Transgenic
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Models, Molecular
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Protease Inhibitors / chemical synthesis
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Protease Inhibitors / chemistry*
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Protease Inhibitors / pharmacology*
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Structure-Activity Relationship
Substances
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Azepines
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Hydroxamic Acids
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Protease Inhibitors
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Amyloid Precursor Protein Secretases