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A CNS targeting prodrug strategy for nuclear receptor modulators-merged.pdf (2.6 MB)
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A CNS-Targeting Prodrug Strategy for Nuclear Receptor Modulators

preprint
submitted on 20.05.2020 and posted on 20.05.2020 by Skylar Ferrara, Thomas Scanlan
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.

Funding

Thyroid Hormone Action

National Institute of Diabetes and Digestive and Kidney Diseases

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Multidisciplinary Training in Neuroendocrinology

National Institute of Diabetes and Digestive and Kidney Diseases

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History

Email Address of Submitting Author

ferrara@ohsu.edu

Institution

Oregon Health & Science University

Country

United States

ORCID For Submitting Author

0000-0001-7826-5621

Declaration of Conflict of Interest

The authors declare the following competing financial interest(s): S.J.F. and T.S.S. are inventors of a licensed patent application claiming central nervous system-penetrating prodrugs of nuclear receptor modulators and their uses. T.S.S. is a founder of Autobahn Therapeutics.

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