title: Prodrugs of peptides. 11. Chemical and enzymatic hydrolysis kinetics of N-acyloxymethyl derivatives of a peptide-like bond.
abstract: Various carboxylic acid esters of the N-hydroxymethyl derivative of N-benzyloxycarbonylglycine benzylamide, used as a peptide-like model, were prepared and their decomposition kinetics studied in aqueous solution and in human plasma solutions. These N-acyloxymethylamide derivatives were found to undergo a facile decomposition by a pH-independent process in the pH range 4-8.5, the half-lives being 1-11hr at 37 degrees C. The cause of this limited stability was suggested to be due to the occurrence of an elimination-addition mechanism involving a reactive N-acylminium ion intermediate. In alkaline solutions (pH greater than 10) the derivatives showed a normal ester stability. The ester group in the N-acyloxymethyl derivatives was readily hydrolyzed by plasma enzymes to yield the N-hydroxymethyl amide, which subsequently decomposed to the parent amide. The results obtained suggest that N-acyloxymethylation of a peptide bond may be a useful prodrug approach to obtain derivatives with varying lipophilicities and a ready ability to undergo conversion to the parent peptide in vivo. However, the stability of the derivatives in aqueous solutions is limited.
authors.affiliation: Royal Danish School of Pharmacy, Department of Pharmaceutical Chemistry, Copenhagen.
authors.forename: H
authors.initials: H
authors.lastname: Bundgaard
authors.forename: G J
authors.initials: GJ
authors.lastname: Rasmussen
mesh_terms: D002851:Chromatography, High Pressure Liquid; D006207:Half-Life; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D010455:Peptides / Q000097:blood / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000493:pharmacokinetics*
chemical_list: D010455:Peptides; D011355:Prodrugs