HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Cyclic Phosphopantothenic Acid Prodrugs for Treatment of Pantothenate Kinase-Associated Neurodegeneration.

Abstract
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.
AuthorsGiulio Auciello, Annalise Di Marco, Odalys Gonzalez Paz, Savina Malancona, Steven Harper, Maria Beconi, Ilaria Rossetti, Alina Ciammaichella, Paola Fezzardi, Andrea Vecchi, Elena Bracacel, Daniel Cicero, Edith Monteagudo, Daniel Elbaum
JournalJournal of medicinal chemistry (J Med Chem) Vol. 63 Issue 24 Pg. 15785-15801 (12 24 2020) ISSN: 1520-4804 [Electronic] United States
PMID33320012 (Publication Type: Journal Article)
Chemical References
  • Prodrugs
  • Pantothenic Acid
  • phosphopantothenic acid
  • Coenzyme A
Topics
  • Animals
  • Blood-Brain Barrier (drug effects, metabolism)
  • Brain (metabolism)
  • Coenzyme A (metabolism)
  • Cyclization
  • Disease Models, Animal
  • Half-Life
  • Hepatocytes (cytology, metabolism)
  • Humans
  • Lipid Droplets (chemistry, metabolism)
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pantothenate Kinase-Associated Neurodegeneration (drug therapy, pathology)
  • Pantothenic Acid (analogs & derivatives, chemistry, metabolism, therapeutic use)
  • Prodrugs (chemistry, metabolism, therapeutic use)
  • Structure-Activity Relationship

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: