RESUMEN
A new class of bicyclic pyrrolopyrimidine-based Janus kinase 3 (JAK-3) inhibitors are described. Many of these inhibitors showed low nanomolar activity against JAK-3.
Asunto(s)
Janus Quinasa 3/antagonistas & inhibidores , Pirimidinas/síntesis química , Pirroles/síntesis química , Enfermedades Autoinmunes/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Inmunidad/efectos de los fármacos , Janus Quinasa 2/antagonistas & inhibidores , Pirimidinas/farmacología , Pirroles/farmacología , Relación Estructura-ActividadRESUMEN
4-Aryl-5-pyrimidyl based cytokine synthesis inhibitors that contain a novel monocyclic, pyrazolone heterocyclic core are described. Many of these inhibitors showed low nanomolar activity against LPS-induced TNF-alpha production. One of the compounds (6e) was found to be efficacious in the rat iodoacetate (RIA) in vivo model of osteoarthritis. The X-ray crystal structure of a pyrazolone inhibitor cocrystallized with mutated p38 (mp38) is presented.
Asunto(s)
Citocinas/antagonistas & inhibidores , Citocinas/biosíntesis , Pirazolonas/síntesis química , Pirazolonas/farmacología , Animales , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Cinética , Lipopolisacáridos/farmacología , Modelos Moleculares , Conformación Molecular , Osteoartritis/prevención & control , Pirazolonas/química , Ratas , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/biosíntesis , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidoresRESUMEN
Novel substituted [5,5]-bicyclic pyrzazolones are presented as inhibitors of tumor necrosis factor-alpha (TNF-alpha) production. Many of these compounds show low nanomolar activity against lipopolysaccaride (LPS)-induced TNF-alpha production in THP-1 cells. This class of molecules was co-crystallized with mutated p38, and several analogs showed good oral bioavailability in the rat. Oral activity of these compounds in the rat iodoacetate model for osteoarthritis is discussed.
Asunto(s)
Pirazolonas/química , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Lipopolisacáridos/farmacología , Modelos Moleculares , Pirazolonas/administración & dosificación , Pirazolonas/farmacocinética , Pirazolonas/farmacología , Ratas , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
2-Aryl-3-pyrimidinyl based tumor necrosis factor-alpha (TNF-alpha) inhibitors, which contain a novel bicyclic pyrazolone core, are described. Many showed low-nanomolar activity against lipopolysaccharide-induced TNF-alpha production in monocytic cells. Secondary screening data are presented for the pyrimidinyl bicyclic pyrazolones. Several of these analogues showed good oral bioavailability in rat and efficacy in the rat iodoacetate in vivo model.
