Design and optimization of a series of 1-sulfonylpyrazolo[4,3-b]pyridines as selective c-Met inhibitors.
J Med Chem
; 58(5): 2513-29, 2015 Mar 12.
Article
em En
| MEDLINE
| ID: mdl-25668160
ABSTRACT
c-Met has emerged as an attractive target for targeted cancer therapy because of its abnormal activation in many cancer cells. To identify high potent and selective c-Met inhibitors, we started with profiling the potency and in vitro metabolic stability of a reported hit 7. By rational design, a novel sulfonylpyrazolo[4,3-b]pyridine 9 with improved DMPK properties was discovered. Further elaboration of π-π stacking interactions and solvent accessible polar moieties led to a series of highly potent and selective type I c-Met inhibitors. On the basis of in vitro and in vivo pharmacological and pharmacokinetics studies, compound 46 was selected as a preclinical candidate for further anticancer drug development.
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1
Base de dados:
MEDLINE
Assunto principal:
Piridinas
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Desenho de Fármacos
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Proteínas Proto-Oncogênicas c-met
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Sistema Enzimático do Citocromo P-450
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Inibidores de Proteínas Quinases
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Neoplasias
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article