title: 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.
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 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.
authors.affiliation: Department of Chemistry, Cephalon, Inc., West Chester, Pennsylvania 19380-4245, USA.
authors.forename: S
authors.initials: S
authors.lastname: Chatterjee
authors.forename: M
authors.initials: M
authors.lastname: Iqbal
authors.forename: S
authors.initials: S
authors.lastname: Mallya
authors.forename: S E
authors.initials: SE
authors.lastname: Senadhi
authors.forename: T M
authors.initials: TM
authors.lastname: O'Kane
authors.forename: B A
authors.initials: BA
authors.lastname: McKenna
authors.forename: D
authors.initials: D
authors.lastname: Bozyczko-Coyne
authors.forename: J C
authors.initials: JC
authors.lastname: Kauer
authors.forename: R
authors.initials: R
authors.lastname: Siman
authors.forename: J P
authors.initials: JP
authors.lastname: Mallamo
mesh_terms: D002154:Calpain / Q000037:antagonists & inhibitors*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured
chemical_list: D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D009842:Oligopeptides; D011994:Recombinant Proteins; D002154:Calpain