Design, synthesis and biological activity evaluation of novel 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl) oxy) pyridine-2-yl) amino derivatives as potent transforming growth factor-ß (TGF-ß) type I receptor inhibitors.
Bioorg Med Chem Lett
; 30(16): 127339, 2020 08 15.
Article
em En
| MEDLINE
| ID: mdl-32631540
ABSTRACT
TGF-ß type I receptor (also known as activin-like kinase 5 or ALK5) plays a critical role in the progression of fibrotic diseases and tumor invasiveness and metastasis, as well. The development of small inhibitors targeting ALK5 has been validated as a potential therapeutic strategy for fibrotic diseases and cancer. Here, we developed various 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl) oxy) pyridine-2-yl) amino derivatives as ALK5 inhibitors. The optimization led to identification of potent and selective ALK5 inhibitors 12r. The compound 12r exhibited strong inhibitory activity both in vitro and in vivo, and pharmacokinetics study showed an oral bioavailability of 57.6%. Thus, compound 12r may provide as new therapeutic option as ALK5 TGF-ßR1 inhibitor.
Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Desenho de Fármacos
/
Inibidores de Proteínas Quinases
/
Receptor do Fator de Crescimento Transformador beta Tipo I
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Bioorg Med Chem Lett
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
China