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

• Published in: Journal of medicinal chemistry Vol. 63; no. 24; pp. 15785 - 15801
• Main Authors: Auciello, Giulio, Di Marco, Annalise, Gonzalez Paz, Odalys, Malancona, Savina, Harper, Steven, Beconi, Maria, Rossetti, Ilaria, Ciammaichella, Alina, Fezzardi, Paola, Vecchi, Andrea, Bracacel, Elena, Cicero, Daniel, Monteagudo, Edith, Elbaum, Daniel
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 24.12.2020; Amer Chemical Soc
• Subjects: Animals; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Brain - metabolism; Chemistry, Medicinal; Coenzyme A - metabolism; Cyclization; Disease Models, Animal; Half-Life; Hepatocytes - cytology; Hepatocytes - metabolism; Humans; Life Sciences & Biomedicine; Lipid Droplets - chemistry; Lipid Droplets - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Pantothenate Kinase-Associated Neurodegeneration - drug therapy; Pantothenate Kinase-Associated Neurodegeneration - pathology; Pantothenic Acid - analogs & derivatives; Pantothenic Acid - chemistry; Pantothenic Acid - metabolism; Pantothenic Acid - therapeutic use; Pharmacology & Pharmacy; Prodrugs - chemistry; Prodrugs - metabolism; Prodrugs - therapeutic use; Science & Technology; Structure-Activity Relationship; DEFICIENCY
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c01531

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.