Cyclic Phosphopantothenic Acid Prodrugs for Treatment of Pantothenate Kinase-Associated Neurodegeneration
| Autor: | Daniel Elbaum, Daniel O. Cicero, Paola Fezzardi, Annalise Di Marco, Steven J. Harper, Savina Malancona, Elena Bracacel, Andrea Vecchi, Ilaria Rossetti, Edith Monteagudo, Alina Ciammaichella, Giulio Auciello, Odalys Gonzalez Paz, Maria G. Beconi |
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| Rok vydání: | 2020 |
| Předmět: |
Vitamin
Knockout Pharmacology Inbred C57BL Pantothenic Acid Pantothenate kinase-associated neurodegeneration Mice Structure-Activity Relationship chemistry.chemical_compound Oral administration Drug Discovery medicine Animals Humans Coenzyme A Prodrugs Gene Pantothenate Kinase-Associated Neurodegeneration Mice Knockout Animal Chemistry Regeneration (biology) Neurodegeneration Brain Lipid Droplets respiratory system Prodrug Blood-Brain Barrier Cyclization Disease Models Animal Half-Life Hepatocytes Mice Inbred C57BL medicine.disease PANK2 Settore CHIM/08 - Chimica Farmaceutica Disease Models Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry. 63:15785-15801 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Mutations in the human PANK2 gene are implicated in neurodegenerative diseases such as pantothenate kinase-associated neurodegeneration (PKAN) and result in low levels of coenzyme-A (CoA) in the CNS due to impaired production of phosphopantothenic acid (PPA) from vitamin B5. Restoration of central PPA levels by delivery of exogenous PPA is a recent strategy to reactivate CoA biosynthesis in PKAN patients. Fosmetpantotenate is an oral PPA prodrug. We report here the development of a new PANk2-/- knockout model that allows CoA regeneration in brain cells to be evaluated and describe two new series of cyclic phosphate prodrugs of PPA capable of regenerating excellent levels of CoA in this system. A proof-of-concept study in mouse demonstrates the potential of this new class of prodrugs to deliver PPA to the brain following oral administration and confirms incorporation of the prodrug-derived PPA into CoA. |
| Databáze: | OpenAIRE |
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