Arylazanylpyrazolone derivatives as inhibitors of mutant superoxide dismutase 1 dependent protein aggregation for the treatment of amyotrophic lateral sclerosis.
J Med Chem
; 56(6): 2665-75, 2013 Mar 28.
Article
em En
| MEDLINE
| ID: mdl-23445362
ABSTRACT
The arylsulfanylpyrazolone and aryloxanylpyrazolone scaffolds previously were reported to inhibit Cu/Zn superoxide dismutase 1 dependent protein aggregation and to extend survival in the ALS mouse model. However, further evaluation of these compounds indicated weak pharmacokinetic properties and a relatively low maximum tolerated dose. On the basis of an ADME analysis, a new series of compounds, the arylazanylpyrazolones, has been synthesized, and structure-activity relationships were determined. The SAR results showed that the pyrazolone ring is critical to cellular protection. The NMR, IR, and computational analyses suggest that phenol-type tautomers of the pyrazolone ring are the active pharmacophore with the arylazanylpyrazolone analogues. A comparison of experimental and calculated IR spectra is shown to be a valuable method to identify the predominant tautomer.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Superóxido Dismutase
/
Pirazolonas
/
Multimerização Proteica
/
Esclerose Lateral Amiotrófica
/
Mutação
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Estados Unidos