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

• Published in: Bioorganic & medicinal chemistry 1998-05, Vol.6 (5), p.509-522
• Main Authors: Chatterjee, S, Iqbal, M, Mallya, S, Senadhi, S E, O'Kane, T M, McKenna, B A, Bozyczko-Coyne, D, Kauer, J C, Siman, R, Mallamo, J P
• Format: Article
• Language: English
• Subjects: Calpain - antagonists & inhibitors; Cysteine Proteinase Inhibitors - chemical synthesis; Cysteine Proteinase Inhibitors - chemistry; Cysteine Proteinase Inhibitors - pharmacology; Dipeptides - chemical synthesis; Dipeptides - chemistry; Dipeptides - pharmacology; Humans; Magnetic Resonance Spectroscopy; Oligopeptides - chemical synthesis; Oligopeptides - chemistry; Oligopeptides - pharmacology; Protein Conformation; Recombinant Proteins - antagonists & inhibitors; Tumor Cells, Cultured
• ISSN: 0968-0896
• DOI: 10.1016/S0968-0896(98)00009-1

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.