title: Prodrugs of peptides. 6. Bioreversible derivatives of thyrotropin-releasing hormone (TRH) with increased lipophilicity and resistance to cleavage by the TRH-specific serum enzyme.
abstract: Bioreversible derivatization of TRH (pGlu-His-Pro-NH2) to protect the tripeptide against rapid enzymatic inactivation in the systemic circulation and to improve the lipophilicity of this highly hydrophilic peptide was performed by N-acylation of the imidazole group of the histidine residue with various chloroformates. Whereas TRH was rapidly hydrolyzed at its pGlu-His bond in human plasma by a TRH-specific pyroglutamyl aminopeptidase serum enzyme, the N-alkoxycarbonyl derivatives were resistant to cleavage by the enzyme. On the other hand, these derivatives are readily bioreversible as the parent TRH is formed quantitatively from the derivatives by spontaneous hydrolysis or by plasma esterase-catalyzed hydrolysis. In addition to protecting the parent TRH against rapid inactivation in the circulation and hence potentially prolonging the duration of action of TRH in vivo, the N-alkoxycarbonyl prodrug derivatives were much more lipophilic than TRH as assessed by octanol-buffer partitioning. This property may enhance prodrug penetration of the blood-brain barrier and various other biomembranes compared to the parent peptide.
authors.affiliation: Royal Danish School of Pharmacy, Department of Pharmaceutical Chemistry, Copenhagen.
authors.forename: H
authors.initials: H
authors.lastname: Bundgaard
authors.forename: J
authors.initials: J
authors.lastname: Møss
mesh_terms: D004355:Drug Stability; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism*; D012995:Solubility; D013329:Structure-Activity Relationship; D013973:Thyrotropin-Releasing Hormone / Q000378:metabolism*
chemical_list: D011355:Prodrugs; D013973:Thyrotropin-Releasing Hormone