1. Academic Validation
  2. Targeting Fatty-Acid Amide Hydrolase with Prodrugs for CNS-Selective Therapy

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

  • ACS Chem Neurosci. 2017 Nov 15;8(11):2468-2476. doi: 10.1021/acschemneuro.7b00239.
J Matthew Meinig 1 Skylar J Ferrara 1 Tania Banerji 1 Tapasree Banerji 1 Hannah S Sanford-Crane 1 Dennis Bourdette 1 Thomas S Scanlan 1
Affiliations

Affiliation

  • 1 Department of Physiology & Pharmacology, and ‡Department of Neurology, Oregon Health & Science University , 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, United States.
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.

Keywords

FAAH; blood−brain barrier; prodrug; sobetirome; thyroid hormone; thyromimetic.

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