Synthesis and characterization of ester-based prodrugs of glucagon-like peptide 1

Biopolymers. 2010;94(4):448-56. doi: 10.1002/bip.21418.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Diabetes Mellitus, Type 2 / drug therapy
  • Diketopiperazines / analysis
  • Diketopiperazines / chemistry
  • Dipeptides / analysis
  • Dipeptides / chemistry
  • Glucagon-Like Peptide 1 / chemical synthesis*
  • Glucagon-Like Peptide 1 / chemistry*
  • Glucagon-Like Peptide 1 / therapeutic use
  • Humans
  • Prodrugs / chemical synthesis*
  • Prodrugs / chemistry*
  • Prodrugs / therapeutic use


  • Diketopiperazines
  • Dipeptides
  • Prodrugs
  • Glucagon-Like Peptide 1