RESUMEN
Scaffold hopping and structure-based drug design were employed to identify substituted 4-aminoquinolines and 4-aminonaphthyridines as potent, small molecule inhibitors of tumor necrosis factor alpha (TNFα). Structure-activity relationships in both the quinoline and naphthyridine series leading to the identification of compound 42 with excellent potency and pharmacokinetic profile are discussed. X-ray co-crystal structure analysis and ultracentrifugation experiments clearly demonstrate that these inhibitors distort the TNFα trimer upon binding, leading to aberrant signaling when the trimer binds to TNF receptor 1 (TNFR1). Pharmacokinetic-pharmacodynamic activity of compound 42 in a TNF-induced IL-6 mouse model and in vivo activity in a collagen antibody-induced arthritis model, where it showed biologic-like in vivo efficacy, will be discussed.
Asunto(s)
Naftiridinas/farmacología , Quinolinas/farmacología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Animales , Artritis Experimental/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Diseño de Fármacos , Femenino , Humanos , Ratones Endogámicos C57BL , Microsomas Hepáticos/metabolismo , Estructura Molecular , Naftiridinas/síntesis química , Naftiridinas/farmacocinética , Naftiridinas/uso terapéutico , Prueba de Estudio Conceptual , Quinolinas/síntesis química , Quinolinas/farmacocinética , Quinolinas/uso terapéutico , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Aberrant Class I PI3K signaling is a key factor contributing to many immunological disorders and cancers. We have identified 4-amino pyrrolotriazine as a novel chemotype that selectively inhibits PI3Kδ signaling despite not binding to the specificity pocket of PI3Kδ isoform. Structure activity relationship (SAR) led to the identification of compound 30 that demonstrated efficacy in mouse Keyhole Limpet Hemocyanin (KLH) and collagen induced arthritis (CIA) models.