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1.
ACS Med Chem Lett ; 5(2): 193-8, 2014 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-24900800

RESUMEN

Starting from clinical candidates Firategrast, Valategrast, and AJM-300, a series of novel macrocyclic platelet collagen receptor α2ß1 antagonists were developed. The amino acid derived low molecular weight 14-18-membered macrocycles turned out to be highly active toward integrin α2ß1 with IC50s in the low nanomolar range. The conformation of the macrocycles was found to be highly important for the activity, and an X-ray crystal structure was obtained to clarify this. Subsequent docking into the metal-ion-dependent adhesion site (MIDAS) of a ß1 unit revealed a binding model indicating key binding features. Macrocycle 38 was selected for further in vitro and in vivo profiling.

2.
J Immunol ; 175(7): 4724-34, 2005 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-16177120

RESUMEN

After infection with Borrelia burgdorferi, humans and mice under certain conditions develop arthritis. Initiation of inflammation is dependent on the migration of innate immune cells to the site of infection, controlled by interactions of a variety of adhesion molecules. In this study, we used the newly synthesized compound S18407, which is a prodrug of the active drug S16197, to analyze the functional importance of alpha4beta1-dependent cell adhesion for the development of arthritis and for the antibacterial immune response. S16197 is shown to interfere specifically with the binding of alpha4beta(1 integrin to its ligands VCAM-1 and fibronectin in vitro. Treatment of B. burgdorferi-infected C3H/HeJ mice with the alpha4beta1 antagonist significantly ameliorated the outcome of clinical arthritis and the influx of neutrophilic granulocytes into ankle joints. Furthermore, local mRNA up-regulation of the proinflammatory mediators IL-1, IL-6, and cyclooxygenase-2 was largely abolished. Neither the synthesis of spirochete-specific Igs nor the development of a Th1-dominated immune response was altered by the treatment. Importantly, the drug also did not interfere with Ab-mediated control of spirochete load in the tissues. These findings demonstrate that the pathogenesis, but not the protective immune response, in Lyme arthritis is dependent on the alpha4beta1-mediated influx of inflammatory cells. The onset of inflammation can be successfully targeted by treatment with S18407.


Asunto(s)
Aminoácidos/farmacología , Imidazoles/farmacología , Integrina alfa4beta1/antagonistas & inhibidores , Enfermedad de Lyme/prevención & control , Compuestos de Fenilurea/farmacología , Animales , Borrelia burgdorferi/efectos de los fármacos , Borrelia burgdorferi/inmunología , Línea Celular Transformada , Células Endoteliales/inmunología , Células Endoteliales/microbiología , Femenino , Fibronectinas/metabolismo , Humanos , Inmunidad Innata/efectos de los fármacos , Células K562 , Leucocitos/inmunología , Enfermedad de Lyme/tratamiento farmacológico , Enfermedad de Lyme/inmunología , Enfermedad de Lyme/fisiopatología , Ratones , Ratones Endogámicos C3H , Profármacos/farmacología , Articulaciones Tarsianas/efectos de los fármacos , Articulaciones Tarsianas/inmunología , Articulaciones Tarsianas/microbiología , Articulaciones Tarsianas/fisiopatología , Células U937 , Molécula 1 de Adhesión Celular Vascular/metabolismo
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