Oxindole-based SYK and JAK3 dual inhibitors for rheumatoid arthritis: designing, synthesis and biological evaluation.
Future Med Chem
; 9(11): 1193-1211, 2017 07.
Article
en En
| MEDLINE
| ID: mdl-28722479
ABSTRACT
AIM:
Autoimmune disorders have complex pathophysiology and focus is laid on the development of multitargeted agents. Two well-established kinases SYK and JAK3, were considered to design dual inhibitors as potential therapeutics using various molecular-modeling approaches. Mehodology Pharmacophore models for SYK and JAK3 were generated using oxindole-based inhibitors. Furthermore, an in-house database was designed that was screened against the best selected models. The obtained hits were employed for docking analysis and subjected to MM-GBSA analysis and molecular dynamic simulation.RESULTS:
Top five oxindole derivatives were synthesized and evaluated for in vitro SYK and JAK3 activity. The most active compound 4a was evaluated for in vivo antiarthritic activity. It showed significant anti-arthritic activity.CONCLUSION:
Thus, the designed inhibitors resulted in potential therapeutic agents for rheumatoid arthritis.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Artritis Experimental
/
Antirreumáticos
/
Janus Quinasa 3
/
Quinasa Syk
/
Indoles
Límite:
Animals
Idioma:
En
Revista:
Future Med Chem
Año:
2017
Tipo del documento:
Article
País de afiliación:
India