Acid-Sensitive Latent Inhibitors for Proteolytic Enzymes: Synthesis and Characterization

Article abstract of DOI:10.1021/jm00126a018

The reaction between peptide aldehydes and acylhydrazones affords derivatives that represent potential prodrugs for selective inhibition of lysosomal enzymes.BzPheal=Ala, obtained from the reaction between N-benzoyl-L-phenylalaninal and N-acetyl-L-alanine hydrazide, has been most carefully studied.When BzPheal=Ala is introduced into ongoing reactions catalyzed by α-chymotrypsin or papain, the rate of these reactions diminishes more rapidly with time than do those of controls lacking BzPheal=Ala.Furthermore, the disparity between run and control is much greater at pH 5 than at pH 7.The extent of inhibition (defined as explained in the text) at pH 5 can exceed that at pH 7 by 25-40-fold.The data are quantitatively explained by a reaction scheme that recognizes three important properties of BzPheal=Ala: (1) It undergoes hydrolysis at pH 5-7 to regenerate N-benzoyl-L-phenylalaninal; (2) the aldehyde thus liberated is a far more potent inhibitor for serine or cysteine proteases than is BzPheal=Ala; and (3) the rate constant for hydrolysis of BzPheal=Ala at pH 5 greatly exceeds that at pH 7.