2 research outputs found
Targeting Fatty-Acid Amide Hydrolase with Prodrugs for CNS-Selective Therapy
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 <i>V</i><sub>max</sub>/<i>K</i><sub>M</sub> 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 (<i>K</i><sub>p</sub>) 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 <i>in vivo</i>. 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