Abstract
Novel 1-(2-acylhydrazinocarbonyl)cycloalkyl carboxamides were designed as peptidomimetic inhibitors of interleukin-1beta converting enzyme (ICE). A short synthesis was developed and moderately potent ICE inhibitors were identified (IC(50) values <100 nM). Most of the synthesized examples were selective for ICE versus the related cysteine proteases caspase-3 and caspase-8, although several dual-acting inhibitors of ICE and caspase-8 were identified. Several of the more potent ICE inhibitors were also shown to inhibit IL-1beta production in a whole cell assay (IC(50) < 500 nM).
MeSH terms
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Amides / chemical synthesis*
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Amides / pharmacology*
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Aminoimidazole Carboxamide / analogs & derivatives
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Aminoimidazole Carboxamide / chemical synthesis*
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Caspase 8
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Caspase Inhibitors*
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Chemistry, Pharmaceutical / methods
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Cysteine Endopeptidases / metabolism
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Drug Industry / methods
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Drug Screening Assays, Antitumor
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Enzyme Inhibitors / pharmacology
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Humans
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Hydrazines / chemical synthesis*
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Hydrazines / pharmacology*
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Inhibitory Concentration 50
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Models, Chemical
Substances
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Amides
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Caspase Inhibitors
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Enzyme Inhibitors
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Hydrazines
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Aminoimidazole Carboxamide
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CASP8 protein, human
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Caspase 8
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Cysteine Endopeptidases