Discovery of 4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amines as potent, selective and orally bioavailable LRRK2 inhibitors.
Bioorg Med Chem Lett
; 28(9): 1615-1620, 2018 05 15.
Article
em En
| MEDLINE
| ID: mdl-29588215
ABSTRACT
Inhibition of LRRK2 kinase activity with small molecules has emerged as a potential novel therapeutic treatment for Parkinson's disease. Herein we disclose the discovery of a 4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amine series as potent LRRK2 inhibitors identified through a kinase-focused set screening. Optimization of the physicochemical properties and kinase selectivity led to the discovery of compound 7, which exhibited potent in vitro inhibition of LRRK2 kinase activity, good physicochemical properties and kinase selectivity across the kinome. Moreover, compound 7 was able to penetrate into the CNS, and in vivo pharmacology studies revealed significant inhibition of Ser935 phosphorylation in the brain of both rats (30 and 100â¯mg/kg) and mice (45â¯mg/kg) following oral administration.
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Base de dados:
MEDLINE
Assunto principal:
Pirimidinas
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Inibidores de Proteínas Quinases
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Descoberta de Drogas
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Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article