Nuclear receptors have emerged as a class of potentially powerful drug targets for neurodegenerative central nervous system (CNS) diseases.   However, blood-brain barrier permeability remains a major impediment for targeted CNS treatment, especially with carboxylic acid-containing drugs, a functional group that is common to many nuclear receptor ligands.  Additionally, nuclear receptors are generally expressed in various peripheral tissues associated with adverse effects which can lead to challenges with achieving a sufficient therapeutic index.  Herein is described a prodrug strategy which directs the biodistribution of parent drug nuclear receptor modulators into the CNS while masking them as functional receptor ligands in the periphery.  We have found that certain amide derivatives of nuclear receptor ligands containing carboxylic acids are good substrates for fatty-acid amide hydrolase (FAAH), an enzyme with enriched expression in the CNS.  FAAH cleavage of these prodrugs in the CNS leads to substantial increases in brain exposure, and brain-to-serum ratio increases up to ~100-fold compared to the ratio of the parent drug.  Structure-activity relationships, FAAH substrate validation, and comparisons of CNS vs peripheral drug action will also be discussed.  Our results demonstrate that this strategy can be generalized to a variety of carboxylic acid-containing drug structures.<br/>

Generalization of a CNS-targeting prodrug strategy for nuclear receptor modulators

256th National Meeting (2018)

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