Neurodegenerative diseases lack a breadth of treatment options due, in part, to the known difficulties associated with a drug’s passage across the blood-brain barrier. In this study, we provide a blueprint for how to get drug-like structures which feature carboxylic acid motifs across the blood-brain barrier, while attenuating their peripheral exposure using a chemical prodrug strategy. This prodrug strategy utilizes endogenous fatty-acid amide hydrolase expressed in the CNS to cleave and release parent drugs for CNS drug action to commence. In particular, we demonstrate the successes and limitations of this prodrug strategy within a series of nuclear receptor modulators, which have shown promise as potential therapeutics for neurodegenerative diseases.
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