Brain-penetrant cyanoindane and cyanotetralin inhibitors of G2019S-LRRK2 kinase activity.
G2019S
Kinase inhibitor
LRRK2
Parkinson’s disease
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 Oct 2023
15 Oct 2023
Historique:
received:
05
11
2022
revised:
10
08
2023
accepted:
19
09
2023
pubmed:
22
9
2023
medline:
22
9
2023
entrez:
21
9
2023
Statut:
ppublish
Résumé
The G2019S variant of LRRK2, which causes an increase in kinase activity, is associated with the occurrence of Parkinson's disease (PD). Potent, mutation-selective, and brain penetrant inhibitors of LRRK2 can suppress the biological effects specific to G2019S-LRRK2 that cause pathogenicity. We report the discovery of a series of cyanoindane and cyanotetralin kinase inhibitors culminating in compound 34 that demonstrated selective inhibition of phosphorylation of LRRK2 in the mouse brain. These novel inhibitors may further enable the precision medicine path for future PD therapeutics.
Identifiants
pubmed: 37734423
pii: S0960-894X(23)00365-7
doi: 10.1016/j.bmcl.2023.129487
pii:
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
129487Informations de copyright
Copyright © 2023 Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.