Abstract
Novel N-arylsulfonyldipeptidyl aldehyde derivatives were prepared by DMSO oxidation from the corresponding dipeptide alcohol, and their potencies as calpain inhibitors were evaluated in vitro. Among them, N-(4-fluorophenylsulfonyl)-l-valyl-l-leucinal (8, SJA6017) potently inhibited calpains. 8 also inhibited cathepsin B and L but did not inhibit other cysteine proteases (interleukin 1beta-converting enzyme), serine proteases (trypsin, chymotrypsin, thrombin, factor VIIa, factor Xa), or proteasome. Preliminary cytotoxicity studies of 8 exhibited a relatively safe profile.
MeSH terms
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Animals
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Blood Proteins / metabolism
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Caco-2 Cells
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Calpain / antagonists & inhibitors*
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Cells, Cultured
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Cytochrome P-450 Enzyme System / biosynthesis
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Dipeptides / chemical synthesis*
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Dipeptides / chemistry
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Dipeptides / pharmacology
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Dogs
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Haplorhini
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Hepatocytes / enzymology
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Humans
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In Vitro Techniques
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Mice
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Microsomes / metabolism
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Permeability
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Protease Inhibitors / chemical synthesis*
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Protease Inhibitors / pharmacology
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Protease Inhibitors / toxicity
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Rats
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Species Specificity
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Structure-Activity Relationship
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Toxicity Tests, Acute
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Toxicity Tests, Chronic
Substances
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Blood Proteins
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Dipeptides
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N-(4-fluorophenylsulfonyl)-L-valyl-L-leucinal
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Protease Inhibitors
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Cytochrome P-450 Enzyme System
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Calpain