RESUMEN
Through medicinal chemistry lead optimization studies focused on calculated properties and guided by X-ray crystallography and computational modeling, potent pan-JNK inhibitors were identified that showed submicromolar activity in a cellular assay. Using in vitro ADME profiling data, 9t was identified as possessing favorable permeability and a low potential for efflux, but it was rapidly cleared in liver microsomal incubations. In a mouse pharmacokinetics study, compound 9t was brain-penetrant after oral dosing, but exposure was limited by high plasma clearance. Brain exposure at a level expected to support modulation of a pharmacodynamic marker in mouse was achieved when the compound was coadministered with the pan-cytochrome P450 inhibitor 1-aminobenzotriazole.
Asunto(s)
Proteína Quinasa 10 Activada por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Animales , Barrera Hematoencefálica/efectos de los fármacos , Técnicas de Química Sintética , Cristalografía por Rayos X , Inhibidores Enzimáticos del Citocromo P-450/química , Inhibidores Enzimáticos del Citocromo P-450/farmacología , Modelos Animales de Enfermedad , Perros , Evaluación Preclínica de Medicamentos/métodos , Semivida , Humanos , Enfermedad de Huntington/tratamiento farmacológico , Enfermedad de Huntington/metabolismo , Concentración 50 Inhibidora , Células de Riñón Canino Madin Darby/efectos de los fármacos , Ratones , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Proteína Quinasa 10 Activada por Mitógenos/química , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Pirazoles/química , Pirimidinas/química , Relación Estructura-ActividadRESUMEN
The purpose of this descriptive study was to determine parents' naturally occurring assistive actions when their child received immunizations. Additional purposes included describing the preparation the parent provided to the child prior to the immunization and parents' plans for assistance following the immunization. The convenience sample included 41 parents (or grandparents) of 40 children between the ages of 18 months and 6 years who were receiving routine immunizations at two urban and five rural clinics in the Midwest. Parents were interviewed regarding plans to assist their child before and after immunization; actual parent-child interactions during immunizations were audiotaped. Data were analyzed descriptively; researchers worked in pairs to achieve 100% inter-rater agreement when coding observations into themes. The parents reported using nine psychological preparation strategies (i.e., procedural information, sensory information, relaxation training, telling the child why the procedure was necessary, and role play) to assist their children in the preparatory phase. Three strategies were used both during (procedural information, distraction, and physical contact) and after (physical contact, praise, and rewards) the immunization. Ten children received no preparation for the immunization; nine of these were younger than 3 years of age. The single most reported source of information to parents about helping their child with immunizations was their physician.