RESUMEN
We report on the nuclear receptor binding affinities, cellular activities of transrepression and transactivation, and anti-inflammatory properties of a quinol-4-one and other A-ring mimetic containing nonsteroidal class of glucocorticoid agonists.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Glucocorticoides/agonistas , Imitación Molecular , Quinolonas/farmacología , Receptores Citoplasmáticos y Nucleares/metabolismo , Transactivadores/farmacología , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Aromatasa/metabolismo , Dexametasona/farmacología , Femenino , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Células HeLa , Humanos , Lipopolisacáridos/farmacología , Ratones , Ratones Endogámicos BALB C , Quinolonas/síntesis química , Quinolonas/química , Transactivadores/síntesis química , Transactivadores/química , Activación TranscripcionalRESUMEN
The tyrosine kinase p56lck (lck) is essential for T cell activation; thus, inhibitors of lck have potential utility as autoimmune agents. Our initial disclosure of a new class of lck inhibitors based on the phenylaminoimidazoisoquinolin-9-one showed reasonable cellular activity but did not work in vivo upon oral administration. Our current work highlights the further use of rational drug design and molecular modeling to produce a series of lck inhibitors that demonstrate cellular activity below 100 nM and are as efficacious as cyclosporin A in an in vivo mouse model of anti-CD3-induced IL-2 production.
Asunto(s)
Bencimidazoles/síntesis química , Inhibidores Enzimáticos/síntesis química , Inmunosupresores/síntesis química , Isoquinolinas/síntesis química , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Administración Oral , Animales , Anticuerpos Monoclonales/farmacología , Bencimidazoles/química , Bencimidazoles/farmacología , Complejo CD3/inmunología , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Femenino , Humanos , Inmunosupresores/química , Inmunosupresores/farmacología , Interleucina-2/antagonistas & inhibidores , Interleucina-2/biosíntesis , Interleucina-2/sangre , Isoquinolinas/química , Isoquinolinas/farmacología , Células Jurkat , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Conformación Molecular , Unión Proteica , Relación Estructura-ActividadRESUMEN
A new class of benzimidazolone p38 MAP kinase inhibitors was discovered through high-throughput screening. X-ray crystallographic data of the lead molecule with p38 were used to design analogues with improved binding affinity and potency in a cell assay of LPS-induced TNFalpha production. Herein, we report the SAR of this new class of p38 inhibitors.