Irreversible inhibition of serine proteases by peptidyl derivatives of alpha-aminoalkylphosphonate diphenyl esters.

Peptidyl alpha-aminoalkylphosphonate diphenyl esters have been synthesized and shown to be effective inhibitors of serine proteases. Extending the peptide chain from a single alpha-aminoalkylphosphonate residue (kobs/[I] = 2.5-260 M-1 s-1) to a tripeptide or tetrapeptide derivative (kobs/[I] = 7,000-17,000 M-1 s-1) resulted in 65-2800 improvement in inhibitory potency and increased specificity. The rate of inactivation of chymotrypsin by MeO-Suc-Ala-Ala-Pro-HNCH(CH2Ph)P(O)(OPh)2 was decreased 5 fold in the presence of the substrate Suc-Val-Pro-Phe-NA (0.119 mM). Phosphonylated serine proteases are extremely stable since the half-life for reactivation was greater than 48 hrs for the inhibited elastases and at least 10 hrs for chymotrypsin.