Characterization of Prodrugs

Abstract

Synthesis of a model peptide GLP1-oxyntomodulin is described to demonstrate that relatively large peptides can be synthesized using methods in the last chapter. The synthesis of Classes 1–4 prodrugs using various drug scaffolds are described. The structural nature of the side chain (especially β branching as evidenced in dipeptides containing valine and tert-butyl glycine); the stereochemistry, and the pKa of the nucleophile serve an important role in determining the relative rate of cleavage. Several fast and slow acting ester prodrug candidates were tested for their potency and were found to have minimal potency as compared to the drug. The prodrugs regained their potencies after incubation in PBS buffer at a pH of 7.2 and temperature of 37 °C.