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A CNS-Targeting Prodrug Strategy for Nuclear Receptor Modulators
Skylar J Ferrara1, Thomas S Scanlan1
1Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, United States.
Journal of Medicinal Chemistry
|August 14, 2020
Summary
This study introduces a prodrug strategy to deliver carboxylic acid drugs, like nuclear receptor modulators, across the blood-brain barrier. The approach utilizes fatty acid amide hydrolase (FAAH) to target central nervous system (CNS) delivery for neurodegenerative diseases.
Area of Science:
- Neuroscience
- Pharmacology
- Drug Delivery
Background:
- The blood-brain barrier (BBB) restricts central nervous system (CNS) drug entry, particularly for carboxylic acid-containing compounds.
- Nuclear receptor modulators are promising for neurodegenerative diseases but face BBB challenges.
- Targeted delivery to the CNS is crucial for effective neurotherapeutics.
Purpose of the Study:
- To develop a prodrug strategy for enhanced CNS penetration of carboxylic acid-based therapeutics.
- To mask peripheral activity while enabling CNS targeting of nuclear receptor modulators.
- To leverage specific enzyme activity within the CNS for prodrug activation.
Main Methods:
- Design of prodrugs with carboxylic acid moieties masked for peripheral circulation.
- Targeting of the enzyme fatty acid amide hydrolase (FAAH), which is enriched in the CNS.
- Evaluation of prodrug biodistribution and CNS penetration in relevant models.
- Assessment of prodrug conversion to active parent drug within the CNS.
Main Results:
- Demonstrated successful masking of peripheral receptor activity.
- Achieved significant CNS biodistribution of the prodrugs.
- Confirmed prodrug activation by CNS-enriched FAAH.
- Validated the strategy across diverse carboxylic acid-containing drug structures.
Conclusions:
- The described prodrug strategy effectively overcomes BBB limitations for CNS therapeutics.
- Targeting FAAH offers a viable route for CNS-specific drug delivery.
- This approach holds potential for treating neurodegenerative CNS diseases with improved efficacy and safety.
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