ALK5 kinase inhibitory activity and synthesis of 2,3,4-substituted 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles.
Eur J Med Chem
; 127: 632-642, 2017 Feb 15.
Article
em En
| MEDLINE
| ID: mdl-28135685
ABSTRACT
A series of 2,3,4-substituted 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles (DPPs) was synthesized and evaluated for their ALK5 inhibition activity. The most potent compounds displayed submicromolar IC50 values for ALK5. Preliminary profiling of one of the most active compounds in a panel of 50 protein kinases revealed its selectivity for ALK5. In cells, the compounds caused dose-dependent dephosphorylation of SMAD2, a well-established substrate of ALK5. In addition, the compounds blocked translocation of SMAD2/3 to nuclei of cells stimulated with TGFß and the protein remained predominantly in cytoplasm, further confirming their molecular target. Therefore, novel DPP derivatives proved to be active as ALK5 inhibitors.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirazóis
/
Desenho de Fármacos
/
Proteínas Serina-Treonina Quinases
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Receptores de Fatores de Crescimento Transformadores beta
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Inibidores de Proteínas Quinases
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Eur J Med Chem
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
República Tcheca