Design of Peptide-Based Prodrug Chemistry and Its Application to Glucagon-like Peptide I

Abstract

Peptide-based drugs are highly effective medicines with relatively short duration of action and of variable therapeutic index. Glucagon-like peptide 1 is a hormone that offers promise in the treatment of Type II diabetes. However, the biggest problem in the therapeutic use of GLP-1 is its extremely short half-life in plasma (~2 min). A prodrug of GLP-1 should extend and improve the pharmacodynamics of this peptide hormone. We have designed prodrugs that slowly convert to the parent drug at physiological conditions of 37C and pH 7.2 driven by their inherent chemical instability without the need of any enzymatic cleavage. We observed that amide prodrugs could not convert to the active peptides under physiological conditions. Consequently, we decided to synthesize peptide drugs which had a hydroxy-terminal extension instead of a Nterminal amine. Ester prodrugs were prepared using these hydroxy-peptides as the scaffold. We explored the diketopiperazine and diketomorpholine (DKP and DMP) strategy for the chemical flexibility that it offers to develop prodrugs with variable time actions. The esters proved to be more labile than the corresponding amides and the dynamic range in rate of cleavage ranged from an hour to almost half a week. We found that the rate of cleavage depends on the structure and stereochemistry of the dipeptide pro-moiety and also on the strength of the nucleophile. The careful selection of appropriate functionality that balances chemical, biological and immunological features under physiological conditions has also been reported.