Potent peptide alpha-ketohydroxamate inhibitors of recombinant human calpain I.
A series of potent dipeptide and tripeptide alpha-ketohydroxamic esters was prepared as inhibitors of recombinant human calpain I. Compound 3c, a Cbz-Leu-Phe hydroxamate, displayed the greatest potency against calpain I (IC(50)=6nM), while two compounds, 3l and 3m, both possessing the Cbz-Leu-Leu-Phe sequence, were the most potent (IC(50)=0.2 microM) in a MOLT-4 cell assay.
Josef
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Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380-4245, USA. kjosef@cephalon.com
Kauer
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Bihovsky
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D002154:Calpain / Q000037:antagonists & inhibitors*; D002463:Cell Membrane Permeability / Q000187:drug effects; D006023:Glycoproteins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007659:Ketones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
D006023:Glycoproteins; D007659:Ketones; D009842:Oligopeptides; D011994:Recombinant Proteins; C039304:calpain inhibitors; D002154:Calpain