Synthesis and structure-activity relationships of pyrazolo-[3,4-b]pyridine derivatives as adenosine 5'-monophosphate-activated protein kinase activators.
Arch Pharm (Weinheim)
; 352(8): e1900066, 2019 Aug.
Article
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| MEDLINE
| ID: mdl-31373047
ABSTRACT
A series of pyrazolo[3,4-b]pyridine derivatives were designed, synthesized, and evaluated for their activation activity toward adenosine 5'-monophosphate-activated protein kinase (AMPK). According to the enzyme activity, the pyrazole N-H exposure and para substitution on the diphenyl group were proved to be essential for the activation potency. Compound 17f showed equal activation compared with A-769662. In the molecular modeling study, compound 17f exhibited important hydrogen bond interaction with Lys29, Asp88, and Arg83. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays on the NRK-49F cell line showed that potent enzyme activators could effectively inhibit cell proliferation, especially for 17f (EC50 [AMPKα1γ1ß1] = 0.42 µM, efficacy = 79%; IC50 [NRK-49F cell line] = 0.78 µM). These results might provide new insights to explore novel AMPK activators.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Pirazoles
/
Piridinas
/
Proteínas Quinasas Activadas por AMP
Límite:
Humans
Idioma:
En
Revista:
Arch Pharm (Weinheim)
Año:
2019
Tipo del documento:
Article
País de afiliación:
China