RESUMEN
Oxadiazole replacement of an amide linkage in an RARα agonist template 1, followed by lead optimisation, has produced a highly potent and selective RARß agonist 4-(5-(4,7-dimethylbenzofuran-2-yl)-1,2,4-oxadiazol-3-yl)benzoic acid (10) with good oral bioavailability in the rat and dog. This molecule increases neurite outgrowth in vitro and induces sensory axon regrowth in vivo in a rodent model of avulsion and crush injury, and thus has the potential for the treatment of nerve injury.
Asunto(s)
Oxadiazoles/química , Receptores de Ácido Retinoico/agonistas , Administración Oral , Animales , Perros , Evaluación Preclínica de Medicamentos , Semivida , Locomoción/efectos de los fármacos , Células de Riñón Canino Madin Darby , Proyección Neuronal/efectos de los fármacos , Traumatismos del Nervio Óptico/tratamiento farmacológico , Oxadiazoles/farmacocinética , Oxadiazoles/farmacología , Ratas , Receptores de Ácido Retinoico/metabolismo , Relación Estructura-ActividadRESUMEN
Alpha-amino phosphonates can be rapidly assembled in moderate to good yields (42-65%) via a "one-pot" process that brings together four components through the construction of three new intermolecular bonds.
Asunto(s)
Aziridinas/química , Organofosfonatos/química , Organofosfonatos/síntesis químicaRESUMEN
Extratropical cyclones (ETCs) are the primary driver of large-scale episodic beach erosion along coastlines in temperate regions. However, key drivers of the magnitude and regional variability in rapid morphological changes caused by ETCs at the coast remain poorly understood. Here we analyze an unprecedented dataset of high-resolution regional-scale morphological response to an ETC that impacted southeast Australia, and evaluate the new observations within the context of an existing long-term coastal monitoring program. This ETC was characterized by moderate intensity (for this regional setting) deepwater wave heights, but an anomalous wave direction approximately 45 degrees more counter-clockwise than average. The magnitude of measured beach volume change was the largest in four decades at the long-term monitoring site and, at the regional scale, commensurate with that observed due to extreme North Atlantic hurricanes. Spatial variability in morphological response across the study region was predominantly controlled by alongshore gradients in storm wave energy flux and local coastline alignment relative to storm wave direction. We attribute the severity of coastal erosion observed due to this ETC primarily to its anomalous wave direction, and call for greater research on the impacts of changing storm wave directionality in addition to projected future changes in wave heights.