James C. Kauer

Potent α-ketocarbonyl and boronic ester derived inhibitors of proteasome

Abstract Potent and selective α-ketocarbonyl ( 8a–b ) and boronic ester ( 11 ) derived inhibitors of the chymotrypsin-like activity of proteasome , first member of a newly identified class of threonine proteases, are described.

XANTHENE DERIVED POTENT NONPEPTIDIC INHIBITORS OF RECOMBINANT HUMAN CALPAIN I

Abstract Novel and potent, xanthene derived reversible aldehyde (7c) and α-ketocarboxamide (10a), and irreversible fluoromethyl ketone (10b) inhibitors of recombinant human calpain I are described.

Inhibition of calpain by peptidyl heterocycles

Abstract Dipeptidyl and tripeptidyl heterocycles designed to mimic peptide ketoanides and ketoacids were prepared and evaluated in vitro as inhibitors of human calpain I. Boc-Leu-Leu-imidazole ( 12 ) inhibited calpain I at low micromolar concentrations.

Exploration of the importance of the P2-P3-NHCO-moiety in a potent di- or tripeptide inhibitor of calpain I: insights into the development of nonpeptidic inhibitors of calpain I.

Calpain I, an intracellular cysteine protease, has been implicated in the neurodegeneration following an episode of cerebral ischemia. In this paper, we report on a series of peptidomimetic ketomethylene and carbamethylene inhibitors of recombinant human calpain I (rh calpain I). Our study reveals that the -NHCO-moiety (possible hydrogen-bonding site) at the P2-P3 region of a potent tripeptide or a dipeptide inhibitor of calpain I is not a strict requirement for enzyme recognition. Compounds 7d ((R)-2-isobutyl-4-oxo-4-(9-xanthenyl)butanoic acid ((S)-1-formyl-3-methyl)butyl amide), 31 ((R)-2-isobutyl-4-(2-sulfonylnaphthyl)butyric acid ((S)1-formyl-3-methyl)butyl amide) and 34 ((R)-2-isobutyl-4-(2-sulfoxylnaphthyl)butyric acid ((S)-1-formyl-3-methyl)butyl amide) which exhibited good activity in the enzyme assay, also inhibited calpain I in a human cell line.