Abstract
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 language | English (US) |
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Pages (from-to) | 9742-9751 |
Number of pages | 10 |
Journal | Journal of Medicinal Chemistry |
Volume | 63 |
Issue number | 17 |
DOIs | |
State | Published - Sep 10 2020 |
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery