Neurodegenerative CNS diseases remain challenging to target therapeutically due to the restriction of drug-like molecules from passing through the blood-brain barrier. Nuclear receptors are important drug targets in the CNS, however, many of their modulators contain polar functional groups like carboxylates for target engagement and thus are inhibited from crossing the blood-brain barrier.  Additionally, isosteric replacement of these groups can improve brain penetration, but adverse peripheral effects mire their advancement in the clinic.  Herein is described the development of a prodrug strategy which can successfully deliver more potent modulator to the brain while attenuating peripheral exposure by conversion of the parent carboxylic acid-containing drugs into amides.  These amide prodrugs not only improve blood-brain barrier passage, but are substrates for a brain-residing amidase called fatty acid amide hydrolase (FAAH) while remaining masked in the periphery. FAAH cleavage of the prodrugs increases brain exposure and brain-to-serum ratios of the parent drugs up to ~100-fold compared to administration of the corresponding parent drug. Physicochemical properties, FAAH substrate validation, and comparisons of CNS vs peripheral drug action will be presented. Our results indicate this strategy can be extended to a variety of relevant carboxylic acid-containing drug structures.

Development of a prodrug strategy for CNS delivery of nuclear receptor modulators

2019 Fall National Meeting

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