Prodrugs of peptides. 19. Protection of the pyroglutamyl residue against pyroglutamyl aminopeptidase by N-acyloxymethylation and other means.
The N-terminal pyroglutamyl group in several peptides is specifically cleaved by pyroglutamyl aminopeptidase (PAPase I). With the aim of protecting this group against enzymatic cleavage by the prodrug approach, various derivatives of L-pyroglutamyl benzylamide, used as a PAPase I sensitive model pyroglutamyl peptide, were prepared and their stability characteristics determined. The derivatives studied included phenoxycarbonyl, phthalidyl, hydroxymethyl and actoxymethyl derivatives, all formed at the pyroglutamyl NH-moiety. Whereas L-pyroglutamyl benzylamide was rapidly hydrolyzed by PAPase I, all the derivatives were resistant to cleavage by the enzyme. On the other hand, these derivatives, with the exception of the N-phenoxycarbonyl derivative, were readily converted to the parent pyroglutamyl benzylamide by spontaneous or plasma catalyzed hydrolysis, the half-lives of conversion in 80% human plasma being in the range 2.3-8.4 h. The major degradation reaction of the N-phenoxycarbonyl derivative in both buffer and plasma solutions was hydrolytic opening of the pyrrolidone ring. The pH-rate profiles for the degradation of the compounds in aqueous solution were obtained and both specific acid and base catalytic reactions as well as a spontaneous reaction were observed. The results suggest that N-phthalidylation, N-hydroxymethylation and N-acyloxymethylation of pyroglutamyl peptides may be useful prodrug approaches to protect such peptides against cleavage by pyroglutamyl aminopeptidase and hence to improve their delivery characteristics.
Møss
J
J
Royal Danish School of Pharmacy, Department of Pharmaceutical Chemistry, Copenhagen, Denmark.
Bundgaard
H
H
D006801:Humans; D066298:In Vitro Techniques; D008745:Methylation; D010455:Peptides / Q000097:blood / Q000138:chemical synthesis*; D011355:Prodrugs / Q000138:chemical synthesis*; D011751:Pyroglutamyl-Peptidase I / Q000097:blood; D011761:Pyrrolidonecarboxylic Acid / Q000737:chemistry*
D010455:Peptides; D011355:Prodrugs; D011751:Pyroglutamyl-Peptidase I; D011761:Pyrrolidonecarboxylic Acid