Prodrugs of peptides. IV: Bioreversible derivatization of the pyroglutamyl group by N-acylation and N-aminomethylation to effect protection against pyroglutamyl aminopeptidase

Abstract

Various N-acyl derivatives and N-Mannich bases of the model compound L-pyroglutamyl benzylamide were synthesized to assess their suitability as prodrug forms for the N-terminal pyroglutamyl residue occurring in several peptides, with the aim of improving peptide delivery characteristics. Whereas pyroglutamyl benzylamide was rapidly hydrolyzed by pyroglutamyl aminopeptidase, the N-acyl derivatives and N-Mannich bases (N-aminomethyl derivatives) were totally resistant to cleavage by the enzyme. On the other hand, these derivatives are readily bioreversible, the conversion to the parent pyroglutamyl amide taking place either by spontaneous hydrolysis at physiological pH, as demonstrated for the N-Mannich bases, or by plasma enzymes, as shown for the N-acyl derivatives. The results suggest that by appropriate N-acylation or N-aminomethylation it may be feasible to protect pyroglutamyl-containing peptides against cleavage by pyroglutamyl aminopeptidase and to obtain a release of the parent peptide in the organism, hence improving the delivery characteristics of such peptides.