RESUMO
Osteoporosis is a disorder in which bone mass decreases and is responsible for many degenerative bone diseases. The excessive formation and activity of osteoclasts results in pathological disorders of the bone. Receptor Activator of Nuclear Factor κB Ligand (RANKL) is regarded as a key regulator of osteoclast activity and as a new therapeutic target for treating osteoporosis. Herein, we have synthesized several new small molecules and tested their inhibition activity on RANKL-induced osteoclast formation. The active compounds 2c and 4d showed inhibitory activity against RANKL-induced osteoclast differentiation (IC50 = 1.56 and 2.20 µM, respectively). The most active compound 2c prevented LPS-induced osteoclastogenesis in vivo. These data imply that the compound may be the potential candidate for a new therapeutic drug for treatment of bone resorption-associated diseases.
Assuntos
Conservadores da Densidade Óssea/farmacologia , Remodelação Óssea/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Éteres/farmacologia , Osteoclastos/efeitos dos fármacos , Animais , Conservadores da Densidade Óssea/síntese química , Remodelação Óssea/genética , Diferenciação Celular/genética , Células Cultivadas , Éteres/síntese química , Regulação da Expressão Gênica , Lipopolissacarídeos/farmacologia , Masculino , Camundongos Endogâmicos ICR , Estrutura Molecular , Osteoclastos/metabolismo , Ligante RANK/farmacologia , Fatores de TempoRESUMO
5-Lipoxygenase synthesizes leukotrienes from arachidonic acid. We developed three novel 5-LO inhibitors having a benzoxazole scaffold as a potential anti-osteoclastogenics. They significantly suppressed RANKL-induced osteoclast formation in mouse bone marrow-derived macrophages. Furthermore, one compound, K7, inhibited the bone resorptive activity of osteoclasts. The anti-osteoclastogenic effect of K7 was mainly attributable to reduction in the expression of NFATc1, an essential transcription factor for osteoclast differentiation. K7 inhibited osteoclast formation via ERK and p38 MAPK, as well as NF-κB signaling pathways. K7 reduced lipopolysaccharide (LPS)-induced osteoclast formation in vivo, corroborating the in vitro data. Thus, K7 exerted an inhibitory effect on osteoclast formation in vitro and in vivo, properties that make it a potential candidate for the treatment of bone diseases associated with excessive bone resorption.
Assuntos
Inibidores de Lipoxigenase/química , Fatores de Transcrição NFATC/metabolismo , Ligante RANK/metabolismo , Animais , Araquidonato 5-Lipoxigenase/química , Araquidonato 5-Lipoxigenase/metabolismo , Sítios de Ligação , Células da Medula Óssea/citologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Humanos , Lipopolissacarídeos/toxicidade , Inibidores de Lipoxigenase/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Osteoclastos/citologia , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , Estrutura Terciária de Proteína , Transdução de Sinais/efeitos dos fármacos , Crânio/efeitos dos fármacos , Crânio/metabolismo , Crânio/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
5-Lipoxygenase (5-LOX) is important enzyme in the biosynthesis of leukotrienes, and is a potential target in the treatment of asthma and allergy. We designed and synthesized a series of benzoxazoles and benzothiazoles as 5-LOX inhibitors. Fourteen compounds prepared showed the inhibition of LTC4 formation with IC(50) value of 0.12-23.88 µM. Also two compounds 2d and 2g showed improved airway hypersensitiveness.
