RESUMEN
Alzheimer's Disease (AD) is the most widespread form of dementia, with one of the pathological hallmarks being the formation of neurofibrillary tangles (NFTs). These tangles consist of phosphorylated Tau fragments. Asparagine endopeptidase (AEP) is a key Tau cleaving enzyme that generates aggregation-prone Tau fragments. Inhibition of AEP to reduce the level of toxic Tau fragment formation could represent a promising therapeutic strategy. Here, we report the first orthosteric, selective, orally bioavailable, and brain penetrant inhibitors with an irreversible binding mode. We outline the development of the series starting from reversible molecules and demonstrate the link between inhibition of AEP and reduction of Tau N368 fragment both in vitro and in vivo.
Asunto(s)
Enfermedad de Alzheimer , Proteínas tau , Humanos , Proteínas tau/metabolismo , Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Ovillos Neurofibrilares/metabolismo , Ovillos Neurofibrilares/patología , FosforilaciónRESUMEN
An extensive fluorine scan of 1,3-oxazines revealed the power of fluorine(s) to lower the pKa and thereby dramatically change the pharmacological profile of this class of BACE1 inhibitors. The CF3 substituted oxazine 89, a potent and highly brain penetrant BACE1 inhibitor, was able to reduce significantly CSF Aß40 and 42 in rats at oral doses as low as 1 mg/kg. The effect was long lasting, showing a significant reduction of Aß40 and 42 even after 24 h. In contrast to 89, compound 1b lacking the CF3 group was virtually inactive in vivo.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Animales , Química Encefálica , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/uso terapéutico , Femenino , Flúor/química , Humanos , Indicadores y Reactivos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Modelos Moleculares , Oxazinas/síntesis química , Oxazinas/farmacología , Ratas , Ratas Wistar , Relación Estructura-Actividad , Difracción de Rayos XRESUMEN
Methyl-triethanol-ammonium originates from the hydrolysis of the parent esterquat surfactant, which is used as softener in fabric care. The initial steps of the catabolism were investigated in cell-free extracts of the bacterial strain MM 1 able to grow with methyl-triethanol-ammonium as sole source of carbon, energy and nitrogen. The initial degradation of methyl-triethanol-ammonium is an enzymatically catalyzed reaction, located in the particulate fraction of strain MM 1. The oxygen dependent reaction occurred also in presence of phenazine methosulfate as an alternative electron acceptor. As soon as one ethanol group of methyl-triethanol-ammonium was oxidized to the aldehyde, cyclic hemiacetals were formed by intramolecular cyclization. The third ethanol group of methyl-triethanol-ammonium was oxidized to the aldehyde and the carboxylic acid sequentially. The structurally related compounds dimethyl-diethanol-ammonium and choline were oxidized as well, whereas (+/-)-2,3-dihydroxypropyl-trimethyl-ammonium was not converted at all. The structures of the metabolites were established by 1D and 2D 1H, 13C and 14N NMR spectroscopy and by capillary electrophoresis mass spectrometry.
