RESUMO
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.
Assuntos
Artrite Reumatoide/tratamento farmacológico , Imidazóis/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Administração Oral , Animais , Artrite Reumatoide/induzido quimicamente , Colágeno , Relação Dose-Resposta a Droga , Imidazóis/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , NF-kappa B/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismoRESUMO
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.
Assuntos
Artrite Experimental/tratamento farmacológico , Imidazolinas/uso terapêutico , NF-kappa B/antagonistas & inibidores , Administração Oral , Animais , Artrite Experimental/imunologia , Imidazolinas/administração & dosagem , Imidazolinas/síntese química , Camundongos , Camundongos Endogâmicos BALB C , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/imunologiaRESUMO
We herein describe the synthesis and anti-inflammatory properties of a small library of imidazoline-based NF-kappaB inhibitors. The structure-activity relationship of various substituents on an imidazoline core structure was evaluated for the ability to inhibit NF-kappaB mediated IL-6 production. Optimization of the scaffolds was pursued by correlating luciferase-based NF-kappaB reporter assays with inhibition of IL-6 production in IL-1beta stimulated human blood. Several derivatives were found to inhibit NF-kappaB mediated IL-6 production in the nanomolar range in IL-1beta stimulated human blood.
Assuntos
Imidazolinas/química , Imidazolinas/farmacologia , Interleucina-6/biossíntese , NF-kappa B/antagonistas & inibidores , Células Cultivadas , Células HeLa , Humanos , Interleucina-1beta/sangue , Interleucina-1beta/farmacologia , Interleucina-6/sangue , NF-kappa B/genética , NF-kappa B/metabolismo , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/farmacologia , Relação Estrutura-Atividade , Ativação Transcricional/efeitos dos fármacosRESUMO
The mammalian nuclear transcription factor NF-kappaB is responsible for the transcription of multiple cytokines, including the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6). Elevated levels of pro-inflammatory cytokines play an important role in the pathogenesis of inflammatory disorders such as rheumatoid arthritis (RA). Inhibition of the pro-inflammatory transcription factor NF-kappaB has therefore been identified as a possible therapeutic treatment for RA. We describe herein the synthesis and biological activity of a series of imidazoline-based scaffolds as potent inhibitors of NF-kappaB mediated gene transcription in cell culture as well as inhibitors of TNF-alpha and IL-6 production in interleukin 1 beta (IL-1beta) stimulated human blood.
