A CNS-Targeting Prodrug Strategy for Nuclear Receptor Modulators

Skylar J. Ferrara, Thomas S. Scanlan

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)9742-9751
Number of pages10
JournalJournal of Medicinal Chemistry
Issue number17
StatePublished - Sep 10 2020

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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