Phosphoramidate derivates as controlled-release prodrugs of l-Dopa.
Parkinson’s disease
Phosphoramidate
Prodrug
l-Dopa
Journal
Bioorganic & medicinal chemistry letters
ISSN: 1464-3405
Titre abrégé: Bioorg Med Chem Lett
Pays: England
ID NLM: 9107377
Informations de publication
Date de publication:
15 09 2019
15 09 2019
Historique:
received:
10
06
2019
accepted:
04
08
2019
pubmed:
12
8
2019
medline:
21
10
2020
entrez:
12
8
2019
Statut:
ppublish
Résumé
l-Dopa has continued to be a mainstay in the symptomatic treatment of Parkinson's disease (PD). However, extensive peripheral metabolism, a short systemic circulation half-life and development of motor complications called dyskinesia prevents its long-term utilization as a PD therapeutic. Herein, we report a series of phosphoramidate derivatives of l-Dopa and controlled release of l-Dopa at pH 7.4 and 3. The kinetic data for the release of l-Dopa support our hypothesis that a proximal carboxylic acid can promote the pH-triggered hydrolysis of the phosphoramidate PN bond. As expected, esterification of the proximal carboxylic acid protects the scaffold from rapid release at low pH. This latter observation is particularly noteworthy as it suggests that the phosphoramidate-based l-Dopa-conjugate scaffold can be adapted for oral administration as an ester prodrug.
Identifiants
pubmed: 31400939
pii: S0960-894X(19)30531-1
doi: 10.1016/j.bmcl.2019.08.005
pmc: PMC7654512
mid: NIHMS1637041
pii:
doi:
Substances chimiques
Amides
0
Antiparkinson Agents
0
Delayed-Action Preparations
0
Phosphoric Acids
0
Prodrugs
0
Levodopa
46627O600J
phosphoramidic acid
9Q189608GB
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2571-2574Subventions
Organisme : NIGMS NIH HHS
ID : T32 GM008336
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Ltd. All rights reserved.
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