Exploration of the importance of the P 2-P 3 -NHCO-Moiety in a potent di- or tripeptide inhibitor of calpain i: insights into the development of nonpeptidic inhibitors of calpain I

Abstract

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 P 2-P 3 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.