RESUMEN
A series of pyrido[2,3-d]pyrimidin-5-ones has been synthesized and evaluated as inhibitors of the kinase domain of macrophage colony-stimulating factor-1 receptor (FMS). FMS inhibitors may be useful in treating rheumatoid arthritis and other chronic inflammatory diseases. Structure-based optimization of the lead amide analogue 10 led to hydroxamate analogue 37, which possessed excellent potency and an improved pharmacokinetic profile. During the chronic phase of streptococcal cell wall-induced arthritis in rats, compound 37 (10, 3, and 1 mg/kg) was highly effective at reversing established joint swelling. In an adjuvant-induced arthritis model in rats, 37 prevented joint swelling partially at 10 mg/kg. In this model, osteoclastogenesis and bone erosion were prevented by low doses (1 or 0.33 mg/kg) that had minimal impact on inflammation. These data underscore the potential of FMS inhibitors to prevent erosions and reduce symptoms in rheumatoid arthritis.
Asunto(s)
Antiinflamatorios/química , Artritis Reumatoide/tratamiento farmacológico , Pirimidinonas/química , Receptor de Factor Estimulante de Colonias de Macrófagos/antagonistas & inhibidores , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Resorción Ósea/prevención & control , Modelos Animales de Enfermedad , Inflamación/tratamiento farmacológico , Osteoclastos/efectos de los fármacos , Farmacocinética , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Estructura Terciaria de Proteína , Pirimidinonas/farmacología , Pirimidinonas/uso terapéutico , Ratas , Relación Estructura-ActividadRESUMEN
A series of pyrimidinopyridones has been designed, synthesized and shown to be potent and selective inhibitors of the FMS tyrosine kinase. Introduction of an amide substituent at the 6-position of the pyridone core resulted in a significant potency increase. Compound 24 effectively inhibited in vivo LPS-induced TNF in mice greater than 80%.