Prodrugs and their activation mechanisms for brain drug delivery

Abstract

Prodrugs are masked drugs that first become pharmacologically active after undergoing a structural change in vivo. They are designed to improve physicochemical/biopharmaceutical drug properties and increase site specificity. The prodrug approach is important when developing brain-targeting drugs due to the presence of the brain barriers that seriously limit the brain entry of highly polar, multifunctional drug entities. While several excellent reviews summarize the structural modifications facilitating transport across the brain barriers, a summary of mechanisms used for the activation of the prodrug in the brain is missing. Given the high need for innovative discoveries in brain drug development, we here review the most important tools being developed since 2000 for CNS prodrug activation.

Fig. 1. Graphical illustration of the prodrug design for brain disorders. Created in https://BioRender.com.

Fig. 2. The ester prodrug design is compromised by esterase in the periphery and/or unspecific hydrolysis. Created in https://BioRender.com.

Fig. 3. Ester prodrugs containing a larger and/or branched alkyl ester show better BBB penetration and lower unspecific hydrolysis. Inspired from ref and . Created partly in https://BioRender.com.

Fig. 4. Although the LAT1 targeting perforin inhibitor prodrug showed improved brain uptake of the prodrug, the unspecific bioconversion reduces the brain specificity. Inspired from ref. . Created partly in https://BioRender.com.

Fig. 5. Aminopeptidase B is responsible for the bioconversion of the majority of the aromatic amino acid prodrugs targeting LAT1. Blue represents the drug while green/orange/red represent the LAT-1 recognition parts. Inspired from ref. .

Fig. 6. Linear, rod-like N-methylamides are good substrates for the brain-selective enzyme FAAH. Inspired from ref. .

Fig. 7. NAD(P)H-dependent short-chain dehydrogenase/reductase (SDR) bioconversion of the prodrugs DHED/α-DHED to the active drugs E₂/α-E₂. Inspired from ref. and .

Fig. 8. NAD(P)H-dependent NAD(P)H/quinone oxidoreductase (NQO1) bioconversion of a bexarotene prodrug. Inspired from ref. .

Fig. 9. The AChEI rivastigmine and tacrine inspired prodrugs: in vivo redox activation initiates a structural rearrangement to form active AChEIs. Inspired from ref. and . Created partly in https://BioRender.com.

Fig. 10. Dual reactive oxygen species (ROS)-responsive prodrug leading to the release of two drugs after 1,6-elimination. Inspired from ref. .

Fig. 11. Graphical illustration of the “lock-in the brain” prodrug design. Created in https://BioRender.com.

Fig. 12. Replacing the His or PGlu in the tripeptide TRH with substituted pyridinium leads to increased uptake in the brain due to the ‘lock’ in effect. Inspired from ref. and . Created partly in https://BioRender.com.

Fig. 13. “Lock-in the brain” design based on the 1,4-dihydroquinoline system combined with a cyclization spacer. Inspired from ref. . Created partly in https://BioRender.com.

Fig. 14. “Lock-in the brain” design based on the disulfide to thiamine conversion. Inspired from ref. and . Created partly in https://BioRender.com.

Ida Aaberg Lillethorup

Andreas Victor Hemmingsen

Katrine Qvortrup