A CNS-Targeting Prodrug Strategy for Nuclear Receptor Modulators

The blood–brain
barrier is a major impediment for targeted
central nervous system (CNS) therapeutics, especially with carboxylic
acid-containing drugs. Nuclear receptor modulators, which often feature
carboxylic acid motifs for target engagement, have emerged as a class
of potentially powerful therapeutics for neurodegenerative CNS diseases.
Herein is described a prodrug strategy that directs the biodistribution
of parent drug nuclear receptor modulators into the CNS while masking
them as functional receptor ligands in the periphery. This prodrug
strategy targets a specific amidase, fatty acid amide hydrolase (FAAH),
an enzyme with enriched expression in the CNS. Our results demonstrate
that this prodrug strategy can be generalized to a variety of carboxylic
acid-containing drug structures that satisfy the structural requirements
of blood–brain barrier diffusion and FAAH substrate recognition.