RESUMEN
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
An imidazo[4,5-h]isoquinolin-7,9-dione (1) was identified as an adenosine 5'-triphosphate competitive inhibitor of lck by high throughput screening. Initial structure-activity relationship studies identified the dichlorophenyl ring and the imide NH as important pharmacophores. A binding model was constructed to understand how 1 binds to a related kinase, hck. These results suggested that removing the gem-dimethyl group and flattening the ring would enhance activity. This was realized by converting 1 to the imidazo[4,5-h]isoquinolin-9-one (20), resulting in an 18-fold improvement in potency against lck and a 50-fold increase in potency in a cellular assay.