Prodrugs of peptides. 5. Protection of the pyroglutamyl residue against pyroglutamyl aminopeptidase by bioreversible derivatization with glyoxylic acid derivatives

Abstract

Various N-hydroxyalkyl and N-acyloxyalkyl derivatives of l-pyroglutamyl benzylamide, used as a model pyroglutamyl peptide, were synthesised by reacting it with glyoxylic acid followed by esterification of the carboxy- or hydroxyl group. Whereas the pyroglutamyl benzylamide was rapidly hydrolyzed by pyroglutamyl aminopeptidase, the glyoxylic acid adducts were totally resistant to cleavage by the enzyme. On the other hand, these derivatives are readily bioreversible, being converted to the parent pyroglutamyl benzylamide by spontaneous or plasma-catalyzed hydrolysis. The stability of the derivatives in aqueous solution as a function of pH was studied. The results suggest that by N- α-hydroxyalkylation or N- α-acyloxyalkylation using glyoxyhc acid or esters or amides thereof it may be feasible to protect pyroglutamyl-containing peptides against cleavage by pyroglutamyl aminopeptidase and hence improve the delivery characteristics of such peptides.