Novel compounds that reverse the disease phenotype in Type 2 Gaucher disease patient-derived cells.
Bioorg Med Chem Lett
; 30(2): 126806, 2020 01 15.
Article
en En
| MEDLINE
| ID: mdl-31757667
ABSTRACT
Gaucher disease (GD) results from inherited mutations in the lysosomal enzyme ß-glucocerobrosidase (GCase). Currently available treatment options for Type 1 GD are not efficacious for treating neuronopathic Type 2 and 3 GD due to their inability to cross the blood-brain barrier. In an effort to identify small molecules which could be optimized for CNS penetration we identified tamoxifen from a high throughput phenotypic screen on Type 2 GD patient-derived fibroblasts which reversed the disease phenotype. Structure activity studies around this scaffold led to novel molecules that displayed improved potency, efficacy and reduced estrogenic/antiestrogenic activity compared to the original hits. Here we present the design, synthesis and structure activity relationships that led to the lead molecule Compound 31.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Bibliotecas de Moléculas Pequeñas
/
Fibroblastos
/
Enfermedad de Gaucher
Límite:
Humans
Idioma:
En
Revista:
Bioorg Med Chem Lett
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2020
Tipo del documento:
Article