RESUMEN
Screening of a library of diverse heterocyclic scaffolds identified substituted quinolines as inhibitors of the human proteasome. The heterocyclic library was prepared via a novel titanium-catalyzed multicomponent coupling reaction, which rendered a diverse set of isoxazoles, pyrimidines, pyrroles, pyrazoles and quinolines. SAR of the parent lead compound indicated that hydrophobic residues on the benzo-moiety significantly improved potency. Lead compound 25 inhibits the chymotryptic-like proteolytic activity of the proteasome (IC50 5.4µM), representing a new class of nonpeptidic, noncovalent proteasome inhibitors.
Asunto(s)
Complejo de la Endopetidasa Proteasomal/metabolismo , Inhibidores de Proteasoma/farmacología , Quinolinas/farmacología , Relación Dosis-Respuesta a Droga , Células HeLa , Humanos , Estructura Molecular , Inhibidores de Proteasoma/síntesis química , Inhibidores de Proteasoma/química , Quinolinas/síntesis química , Quinolinas/química , Relación Estructura-ActividadRESUMEN
The pathogenesis of rheumatoid arthritis is mainly driven by NF-κB-mediated production of cytokines, such as TNF-α. We report herein that the orally available imidazoline-based NF-κB inhibitor, TCH-013, was found to significantly reduce TNF-α signaling and attenuate collagen antibody induced arthritis in BALB/c mice.
Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Imidazoles/farmacología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Administración Oral , Animales , Artritis Reumatoide/inducido químicamente , Colágeno , Relación Dosis-Respuesta a Droga , Imidazoles/administración & dosificación , Ratones , Ratones Endogámicos BALB C , Estructura Molecular , FN-kappa B/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The pathogenesis of rheumatoid arthritis is mainly driven by NF-κB-mediated production of cytokines, such as TNF-α. We report herein that the orally available imidazoline-based NF-κB inhibitor, TCH-013, was found to significantly reduce TNF-α signaling and attenuate collagen antibody induced arthritis in BALB/c mice.
Asunto(s)
Artritis Experimental/tratamiento farmacológico , Imidazolinas/uso terapéutico , FN-kappa B/antagonistas & inhibidores , Administración Oral , Animales , Artritis Experimental/inmunología , Imidazolinas/administración & dosificación , Imidazolinas/síntesis química , Ratones , Ratones Endogámicos BALB C , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
The proteasome has emerged as the primary target for the treatment of multiple myeloma. Unfortunately, nearly all patients develop resistance to competitive-type proteasome inhibitors such as bortezomib. Herein, we describe the optimization of noncompetitive proteasome inhibitors to yield derivatives that exhibit nanomolar potency (compound 49, IC50 130 nM) toward proteasome inhibition and overcome bortezomib resistance. These studies illustrate the feasibility of the development of noncompetitive proteasome inhibitors as additives and/or alternatives to competitive proteasome inhibitors.