Novel Peptidyl Phosphorus Derivatives as Inhibitors of Human Calpain I

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Abstract
Dipeptidyl phosphorus compounds were synthesized as potential bioisosteric mimics of peptide α-ketoesters and α-ketoacids. α-Ketophosphonate Cbz-Leu-Leu-P(O)(OCH3)2 (1b), containing an α-ketoester bioisostere, inhibits human calpain I with an IC50 = 0.43 μM. The potency of 1b compares very favorably with that of α-ketoester Cbz-Leu-Leu-CO2Et (IC50 = 0.60 μM). Monomethyl ketophosphonate Cbz-Leu-Leu-P(O)(OH)(OCH3) (1a, IC50 = 5.2 μM), an α-ketoacid mimic, is less potent. Dibutyl and dibenzyl α-ketophosphonates 1c,e,f are much less potent calpain inhibitors than dimethyl α-ketophosphonate 1b. α-Ketophosphinate 1g (IC50 = 0.37 μM) and α-ketophosphine oxide 1h (IC50 = 0.35 μM) are also potent calpain inhibitors.