title: Synthesis and characterization of ester-based prodrugs of glucagon-like peptide 1.
abstract: Peptides represent a rich natural source of potential medicines with one notable pharmaceutical limitation being their relatively short duration of action. A particularly good example of this phenomenon is glucagon-like peptide 1 (GLP), a hormone of appreciable interest for the treatment of type II diabetes. In the native form, GLP demonstrates an extremely short half-life in plasma and a relatively narrow therapeutic index with gastrointestinal adverse pharmacology. We envisioned a prodrug of GLP as a means to extend the duration of action and broaden the therapeutic index of this peptide hormone. We designed, synthesized, and characterized ester-based prodrugs of GLP that differentially convert to the parent drug under physiological conditions driven by their inherent chemical instability. In a set of dipeptide extended GLP-analogs we explored the rate of diketopiperazine (DKP) and diketomorpholine (DMP) formation, and the release of the active peptide. The rate of cleavage was observed to be a function of the conformation of the dipeptide promoiety and the strength of the cyclization nucleophile. Through the careful selection of chemical functionality, a set of GLP ester prodrugs of variable half-lives has been identified.
authors.affiliation: Department of Chemistry, Indiana University, Bloomington, IN 47405, USA.
authors.forename: Arnab
authors.initials: A
authors.lastname: De
authors.forename: Richard D
authors.initials: RD
authors.lastname: DiMarchi
mesh_terms: D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D054659:Diketopiperazines / Q000032:analysis / Q000737:chemistry; D004151:Dipeptides / Q000032:analysis / Q000737:chemistry; D052216:Glucagon-Like Peptide 1 / Q000138:chemical synthesis* / Q000737:chemistry* / Q000627:therapeutic use; D006801:Humans; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry* / Q000627:therapeutic use
chemical_list: D054659:Diketopiperazines; D004151:Dipeptides; D011355:Prodrugs; D052216:Glucagon-Like Peptide 1