| abstract |
This invention relates to analogs of peptidase substrates in which the nitrogen atom of the scissile amide group of the substrate peptide has been replaced by a substituted malonyl moiety. The contemplated peptidase inhibitors of the foregoing enzymes are selected from the generic formula <CHEM> the hydrates, isosteres or the pharmaceutically acceptable salts thereof wherein X is <CHEM> R1 is hydrogen, an amino protecting group selected from Group K, an alpha -amino acid or a peptide comprised of a number of alpha -amino acid building blocks, said alpha -amino acid or peptide optionally bearing on its terminal nitrogen atom an amino protecting group selected from Group K, R2 is the "R group" residue of the alpha -amino acid responsible for directing the inhibitor to the active site of the enzyme or is -A-SiR7R8R9, C1-10 alkyl, aralkyl or aryl with R7, R8 and R9, each being selected from C1-10, alkyl, aralkyl or aryl and A is a C1-6 alkylene, R4 is the specific R-group residue of the alpha -amino acid for that peptidase substrate analog, R5 is an alpha -amino acid or peptide comprised of alpha -amino acids or is deleted, Y is NHR3 or OR3 with R3 being H, C1-7 alkyl, benzyl or phenethyl. These analogs of the peptidase substrates provide specific enzyme inhibitors for a variety of proteases, the inhibition of which will have useful physiological consequences in a variety of disease states. |