Discovery of a 3-(4-Pyrimidinyl) Indazole (MLi-2), an Orally Available and Selective Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitor that Reduces Brain Kinase Activity.
J Med Chem
; 60(7): 2983-2992, 2017 04 13.
Article
en En
| MEDLINE
| ID: mdl-28245354
ABSTRACT
Leucine-rich repeat kinase 2 (LRRK2) is a large, multidomain protein which contains a kinase domain and GTPase domain among other regions. Individuals possessing gain of function mutations in the kinase domain such as the most prevalent G2019S mutation have been associated with an increased risk for the development of Parkinson's disease (PD). Given this genetic validation for inhibition of LRRK2 kinase activity as a potential means of affecting disease progression, our team set out to develop LRRK2 inhibitors to test this hypothesis. A high throughput screen of our compound collection afforded a number of promising indazole leads which were truncated in order to identify a minimum pharmacophore. Further optimization of these indazoles led to the development of MLi-2 (1) a potent, highly selective, orally available, brain-penetrant inhibitor of LRRK2.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Inhibidores Enzimáticos
/
Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina
/
Indazoles
Límite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2017
Tipo del documento:
Article
País de afiliación:
Estados Unidos