Targeting Fatty-Acid Amide Hydrolase with Prodrugs for CNS-Selective Therapy
| Autor: | Tapasree Banerji, Skylar J. Ferrara, Hannah Sanford-Crane, Tania Banerji, Thomas S. Scanlan, J. Matthew Meinig, Dennis Bourdette |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Physiology Oleic Acids Acetates Pharmacology Biochemistry Substrate Specificity Activation Metabolic Mice chemistry.chemical_compound 0302 clinical medicine Fatty acid amide hydrolase Prodrugs Tissue Distribution Sobetirome Mice Knockout Molecular Structure Chemistry Hydrolysis General Medicine Anandamide Prodrug Endocannabinoid system Recombinant Proteins medicine.anatomical_structure Blood-Brain Barrier Organ Specificity lipids (amino acids peptides and proteins) Thyroid Hormones Polyunsaturated Alkamides Cognitive Neuroscience Arachidonic Acids Blood–brain barrier Article Amidohydrolases 03 medical and health sciences Phenols In vivo medicine Animals Humans Distribution (pharmacology) Brain Chemistry Cell Biology Amides Mice Inbred C57BL 030104 developmental biology nervous system 030217 neurology & neurosurgery Endocannabinoids |
| Zdroj: | ACS Chemical Neuroscience. 8:2468-2476 |
| ISSN: | 1948-7193 |
| DOI: | 10.1021/acschemneuro.7b00239 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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