RESUMEN
We developed an automated technique based on the detection of pain-related behaviours (like licking or biting) and small activities (mostly grooming) in the formalin pain test. By comparing automated and manual scoring, we determined that the interphase score was mostly independent of pain-related behaviours and it was used as an index of sedative events. The non-pain-related behaviours, still present during the second phase, were eliminated in order to visualize only pain-related behaviours. This new method, validated using classical analgesic (morphine) and sedative drugs (diazepam) could be used to discriminate sedative from analgesic effects of pharmacological treatments in the formalin test.
Asunto(s)
Analgésicos/farmacología , Hipnóticos y Sedantes/farmacología , Dimensión del Dolor/métodos , Animales , Automatización , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
LFA-1 (leukocyte function-associated antigen-1), is a member of the beta2-integrin family and is expressed on all leukocytes. This letter describes the discovery and preliminary SAR of spirocyclic hydantoin based LFA-1 antagonists that culminated in the identification of analog 8 as a clinical candidate. We also report the first example of the efficacy of a small molecule LFA-1 antagonist in combination with CTLA-4Ig in an animal model of transplant rejection.
Asunto(s)
Antígeno-1 Asociado a Función de Linfocito/metabolismo , Compuestos de Espiro/síntesis química , Tiofenos/síntesis química , Animales , Adhesión Celular/efectos de los fármacos , Cristalografía por Rayos X , Perros , Rechazo de Injerto/prevención & control , Humanos , Antígeno-1 Asociado a Función de Linfocito/química , Ratones , Modelos Moleculares , Estructura Molecular , Neumonía/tratamiento farmacológico , Neumonía/inmunología , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/farmacología , Estereoisomerismo , Relación Estructura-Actividad , Tiofenos/farmacocinética , Tiofenos/farmacología , Trasplante HomólogoRESUMEN
LFA-1 (leukocyte function-associated antigen-1), is a member of the beta(2)-integrin family and is expressed on all leukocytes. The LFA-1/ICAM interaction promotes tight adhesion between activated leukocytes and the endothelium, as well as between T cells and antigen-presenting cells. Evidence from both animal models and clinical trials provides support for LFA-1 as a target in several different inflammatory diseases. This paper describes the de novo design, synthesis and in vitro activity of LFA-1 antagonists based on a bicyclic[5.5]hydantoin scaffold.
