Discovery of potent azaindazole leucine-rich repeat kinase 2 (LRRK2) inhibitors possessing a key intramolecular hydrogen bond - Part 2.
Bioorg Med Chem Lett
; 29(4): 674-680, 2019 02 15.
Article
em En
| MEDLINE
| ID: mdl-30522953
ABSTRACT
The discovery of disease-modifying therapies for Parkinson's Disease (PD) represents a critical need in neurodegenerative medicine. Genetic mutations in LRRK2 are risk factors for the development of PD, and some of these mutations have been linked to increased LRRK2 kinase activity and neuronal toxicity in cellular and animal models. As such, research towards brain-permeable kinase inhibitors of LRRK2 has received much attention. In the course of a program to identify structurally diverse inhibitors of LRRK2 kinase activity, a 5-azaindazole series was optimized for potency, metabolic stability and brain penetration. A key design element involved the incorporation of an intramolecular hydrogen bond to increase permeability and potency against LRRK2. This communication will outline the structure-activity relationships of this matched pair series including the challenge of obtaining a desirable balance between metabolic stability and brain penetration.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina
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Indazóis
Tipo de estudo:
Prognostic_studies
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Risk_factors_studies
Idioma:
En
Revista:
Bioorg Med Chem Lett
Assunto da revista:
BIOQUIMICA
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QUIMICA
Ano de publicação:
2019
Tipo de documento:
Article