Abstract
Novel benzoylalanine-derived ketoamides were prepared and evaluated for calpain I inhibition. Derivatives carrying vinylbenzyl amino residues in the P(2)-P(3) region inhibited calpain in nanomolar concentrations and thus represent a novel class of nonpeptidic calpain inhibitors. Selected examples exhibited an improved pharmacokinetic profile including improved water-solubility and metabolic stability. In particular, these calpain inhibitors showed oral bioavailability in rats as demonstrated by N-(1-benzyl-2-carbamoyl-2-oxoethyl)-2-[E-2-(4-diethylaminomethylphenyl)ethen-1-yl]benzamide (5d). The closely related derivative N-(1-carbamoyl-1-oxohex-1-yl)-2-[E-2-(4-dimethylaminomethylphenyl)-ethen-1-yl]benzamide (5b) was evaluated for neuroprotective efficacy after experimental traumatic brain injury in a fluid percussion model in rats. When administered after injury, 5b reduced the number of damaged neurons by 41%, and this result would be in line with the suggested neuroprotective efficacy of calpain inhibition.
MeSH terms
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Administration, Oral
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Alanine / analogs & derivatives*
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Alanine / chemical synthesis*
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Alanine / pharmacokinetics
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Alanine / pharmacology
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Animals
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Benzene Derivatives / chemical synthesis*
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Benzene Derivatives / pharmacokinetics
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Benzene Derivatives / pharmacology
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Biological Availability
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Blood Platelets / drug effects
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Blood Platelets / metabolism
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Brain Injuries / drug therapy
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Brain Injuries / pathology
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Calpain / antagonists & inhibitors*
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Cell Survival / drug effects
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Cysteine Proteinase Inhibitors / chemical synthesis*
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Cysteine Proteinase Inhibitors / pharmacokinetics
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Cysteine Proteinase Inhibitors / pharmacology
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Dentate Gyrus / drug effects
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Dentate Gyrus / pathology
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Humans
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In Vitro Techniques
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Male
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Neuroprotective Agents / chemical synthesis*
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Neuroprotective Agents / pharmacokinetics
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Neuroprotective Agents / pharmacology
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Proto-Oncogene Proteins pp60(c-src) / metabolism
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Rats
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Rats, Sprague-Dawley
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Solubility
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Stereoisomerism
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Structure-Activity Relationship
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Vinyl Compounds / chemical synthesis*
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Vinyl Compounds / pharmacokinetics
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Vinyl Compounds / pharmacology
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Water
Substances
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Benzene Derivatives
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Cysteine Proteinase Inhibitors
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Neuroprotective Agents
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Vinyl Compounds
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Water
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Proto-Oncogene Proteins pp60(c-src)
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Calpain
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Alanine