Abstract
Peptidomimetic compounds possessing a caprolactam ring constraint were prepared and evaluated as interleukin-1beta converting enzyme (ICE) inhibitors. The caprolactam ring was used to constrain the P3 region of our inhibitors. This strategy proved to be effective for the synthesis of ICE inhibitors, maintaining key hydrogen bond interactions with the enzyme and invoking a preferred conformation for binding. Several compounds exhibited IC(50) values less than 10nM in a caspase-1 enzyme assay and less than 100nM in a THP-1 whole cell assay measuring IL-1beta production. Two compounds, 13c and 13j, were found to have good oral bioavailability (>50%) in rats when administered as prodrugs.
MeSH terms
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Animals
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Biological Availability
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Caprolactam / chemical synthesis*
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Caprolactam / chemistry
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Caprolactam / pharmacology
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Caspase Inhibitors*
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Crystallography, X-Ray
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Hydrogen Bonding
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Interleukin-1beta / metabolism
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Male
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Models, Molecular
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Molecular Conformation
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Molecular Structure
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Rats
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Rats, Sprague-Dawley
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Serpins / chemical synthesis*
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Serpins / pharmacology
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Structure-Activity Relationship
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Viral Proteins / chemical synthesis*
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Viral Proteins / pharmacology
Substances
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Caspase Inhibitors
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Enzyme Inhibitors
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Interleukin-1beta
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Serpins
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Viral Proteins
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Caprolactam
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interleukin-1beta-converting enzyme inhibitor