The expanding role of prodrugs in contemporary drug design and development

Abstract

Prodrugs are molecules with little or no pharmacological activity that are converted to the active parent drug in vivo by enzymatic or chemical reactions or by a combination of the two. Prodrugs have evolved from being serendipitously discovered or used as a salvage effort to being intentionally designed. Such efforts can avoid drug development challenges that limit formulation options or result in unacceptable biopharmaceutical or pharmacokinetic performance, or poor targeting. In the past 10 years, the US Food and Drug Administration has approved at least 30 prodrugs, which accounts for more than 12% of all approved small-molecule new chemical entities. In this Review, we highlight prodrug design strategies for improved formulation and pharmacokinetic and targeting properties, with a focus on the most recently marketed prodrugs. We also discuss preclinical and clinical challenges and considerations in prodrug design and development.

Structural basis for prodrug recognition by the SLC15 family of proton coupled peptide transporters

“…Our understanding of which scaffolds make optimal candidates for prodrug development is still evolving (6, 22). However, the comparison of the three ligands in PepT Sh , and their analysis with respect to peptides bound in PepT St , suggests that common points of interaction between the transporter and different ligands exist, which may present a novel route for prodrug scaffold design.…”

“…The development of prodrugs has progressed with the aim of improving drug pharmacokinetics by overcoming various barriers that reduce clinical efficacy, such as poor oral bioavailaibility or cellular toxicity due to adverse drug-drug interactions (1). Carrier mediated prodrug design has been successfully employed to overcome these challenges (6), however prodrug design remains difficult owing to the lack of a generally applicable strategy that can be broadly applied. The unusual promiscuity of PepT1 and PepT2 make them ideal targets for prodrug development (7).…”

Mannose‐Functionalized Nanoscaffolds for Targeted Delivery in Biomedical Applications

“…Since many drugs are poorly absorbed from the gastrointestinal tract, prodrugs have been designed to allow the compounds to be convertedi nto active forms within the body for improved bioavailability. [47] Chen et al reported mannosylated glutathione (GSH)-responsive nanovesicles self-assembled by chlorambucil prodrug with af luorescencer eporter,g iven that the increaseda mount of reducing equivalents counteract the ROS effects inside cancerc ells. [48] The cleavage of linkage between the anticancer reagent chlorambucil and the fluorescence reporter by intracellular GSH reduction can disassemble the vesicles,t hus leading to the drug releasea nd fluorescence shift, which can be applied to intracellular monitoring.…”

Polyacrylamide grafted Eucalyptus camaldulensis (EC-g-PAM) gum as an efficient binding agent in drug formulations

“…Advanced drug formulation strategies empower the pharmaceutical sphere with all the realistic tools required to develop and formulate up-to-date drug systems day-by-day with a view to comply with the up surging therapeutic demands [4,5]. At the moment, nearly all drug manufacturing approaches predominantly incorporate inert pharmaceutical excipients mainly as binders, in conjunction with pharmacologically active ingredients to achieve extended release of therapeutic agents in finalized dosage designs [6,7]. For the most part, binders are employed in formulations to impart adequate mechanical characteristics by enhancing the adhesion and cohesion existing between individual components of powdered mixtures, as a consequence promoting the toughness of the finalized formulations produced [8,9].…”