Synthesis and biological evaluation of 4-(pyridin-4-oxy)-3-(3,3-difluorocyclobutyl)-pyrazole derivatives as novel potent transforming growth factor-ß type 1 receptor inhibitors.
Eur J Med Chem
; 198: 112354, 2020 Jul 15.
Article
em En
| MEDLINE
| ID: mdl-32387837
ABSTRACT
Inhibition of transforming growth factor ß (TGF-ß) type 1 receptor (ALK5) provides a feasible approach for the treatment of fibrotic diseases and malignant tumors. In this study, we designed and synthesized a new series of 4-(pyridin-4-oxy)-3-(3,3-difluorocyclobutyl)-pyrazole derivatives, and evaluated biologically as TGF-ß type 1 receptor inhibitors. The most potent compound 15r inhibited the ALK5 enzyme and NIH3T3 cell viability with IC50 values of 44 and 42.5 nM, respectively. Compound 15r also displayed better oral plasma exposure and excellent bioavailability than LY-3200882, and in vivo inhibited 65.7% of the tumor growth in a CT26 xenograft mouse model.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirazóis
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Fibrose
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Inibidores de Proteínas Quinases
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Receptor do Fator de Crescimento Transformador beta Tipo I
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Neoplasias
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Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Eur J Med Chem
Ano de publicação:
2020
Tipo de documento:
Article