Targeting Fatty-Acid Amide Hydrolase with Prodrugs for CNS-Selective Therapy

J. Matthew Meinig, Skylar J. Ferrara, Tania Banerji, Tapasree Banerji, Hannah S. Sanford-Crane, Dennis Bourdette, Thomas (Tom) Scanlan

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

The blood-brain barrier (BBB) can be a substantial impediment to achieving therapeutic levels of drugs in the CNS. Certain chemical functionality such as the carboxylic acid is a general liability for BBB permeability preventing significant CNS distribution of a drug from a systemic dose. Here, we report a strategy for CNS-selective distribution of the carboxylic acid containing thyromimetic sobetirome using prodrugs targeted to fatty-acid amide hydrolase (FAAH), which is expressed in the brain. Two amide prodrugs of sobetirome were shown to be efficient substrates of FAAH with Vmax/KM values comparable to the natural endocannabinoid FAAH substrate anandamide. In mice, a systemic dose of sobetirome prodrug leads to a substantial ∼60-fold increase in brain distribution (Kp) of sobetirome compared to an equimolar systemic dose of the parent drug. The increased delivery of sobetirome to the brain from the prodrug was diminished by both pharmacological inhibition and genetic deletion of FAAH in vivo. The increased brain exposure of sobetirome arising from the prodrug corresponds to ∼30-fold increased potency in brain target engagement compared to the parent drug. These results suggest that FAAH-targeted prodrugs can considerably increase drug exposure to the CNS with a concomitant decrease in systemic drug levels generating a desirable distribution profile for CNS acting drugs.

Original languageEnglish (US)
Pages (from-to)2468-2476
Number of pages9
JournalACS Chemical Neuroscience
Volume8
Issue number11
DOIs
StatePublished - Nov 15 2017

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Keywords

  • blood-brain barrier
  • FAAH
  • prodrug
  • sobetirome
  • thyroid hormone
  • thyromimetic

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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