Pyrazole Ureas as Low Dose, CNS Penetrant Glucosylceramide Synthase Inhibitors for the Treatment of Parkinson's Disease.
Journal
ACS medicinal chemistry letters
ISSN: 1948-5875
Titre abrégé: ACS Med Chem Lett
Pays: United States
ID NLM: 101521073
Informations de publication
Date de publication:
09 Feb 2023
09 Feb 2023
Historique:
received:
11
10
2022
accepted:
04
01
2023
pmc-release:
09
02
2024
entrez:
16
2
2023
pubmed:
17
2
2023
medline:
17
2
2023
Statut:
epublish
Résumé
Parkinson's disease is the second most prevalent progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. Loss-of-function mutations in GBA, the gene that encodes for the lysosomal enzyme glucosylcerebrosidase, are a major genetic risk factor for the development of Parkinson's disease potentially through the accumulation of glucosylceramide and glucosylsphingosine in the CNS. A therapeutic strategy to reduce glycosphingolipid accumulation in the CNS would entail inhibition of the enzyme responsible for their synthesis, glucosylceramide synthase (GCS). Herein, we report the optimization of a bicyclic pyrazole amide GCS inhibitor discovered through HTS to low dose, oral, CNS penetrant, bicyclic pyrazole urea GCSi's with
Identifiants
pubmed: 36793422
doi: 10.1021/acsmedchemlett.2c00441
pmc: PMC9923837
doi:
Types de publication
Journal Article
Langues
eng
Pagination
146-155Informations de copyright
© 2023 American Chemical Society.
Déclaration de conflit d'intérêts
The authors declare no competing financial interest.
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