Novel peptidyl phosphorus derivatives as inhibitors of human calpain I

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