RESUMEN
Senile plaques and neurofibrillary tangles are prominent neuropathological hallmarks in Alzheimer's disease and are considered to be targets for therapeutic intervention as well as biomarkers for diagnostic in vivo imaging agents. While there are a number of amyloid-ß positron emission tomography (PET) tracers currently in different stages of clinical development and commercialization, there have been very few reports on imaging agents selectively targeting tau aggregates. In search of [18F]-PET tracers that possess great binding affinity and selectivity toward tau tangles, we tested more than 900 compounds utilizing a unique screening process. A competitive autoradiography assay was set up to test compounds for binding to native tau tangles and amyloid-ß plaques on human brain tissue sections. In our in vitro assays, the 18F labeled compound [18F]-T808 displayed a high level of binding affinity and good selectivity for tau aggregates over amyloid-ß plaques. [18F]-T808 showed rapid uptake and washout in rodent brains. Our in vitro and preclinical in vivo studies suggest that [18F]-T808 possesses suitable properties and characteristics to be a specific and selective PET probe for imaging of paired helical filament tau in human brains.
Asunto(s)
Radioisótopos de Flúor , Tomografía de Emisión de Positrones/métodos , Radiofármacos , Proteínas tau , Péptidos beta-Amiloides/metabolismo , Animales , Autorradiografía/métodos , Radioisótopos de Flúor/metabolismo , Humanos , Ratones , Ratones Endogámicos ICR , Placa Amiloide/diagnóstico por imagen , Placa Amiloide/metabolismo , Unión Proteica/fisiología , Radiofármacos/química , Radiofármacos/metabolismo , Ratas , Ratas Sprague-Dawley , Proteínas tau/metabolismoRESUMEN
Oral delivery of previously disclosed purine and benzimidazole fructose-1,6-bisphosphatase (FBPase) inhibitors via prodrugs failed, which was likely due to their high molecular weight (>600). Therefore, a smaller scaffold was desired, and a series of phosphonic acid-containing thiazoles, which exhibited high potency against human liver FBPase (IC(50) of 10-30 nM) and high selectivity relative to other 5'-adenosinemonophosphate (AMP)-binding enzymes, were discovered using a structure-guided drug design approach. The initial lead compound (30j) produced profound glucose lowering in rodent models of type 2 diabetes mellitus (T2DM) after parenteral administration. Various phosphonate prodrugs were explored without success, until a novel phosphonic diamide prodrug approach was implemented, which delivered compound 30j with good oral bioavailability (OBAV) (22-47%). Extensive lead optimization of both the thiazole FBPase inhibitors and their prodrugs culminated in the discovery of compound 35n (MB06322) as the first oral FBPase inhibitor advancing to human clinical trials as a potential treatment for T2DM.
Asunto(s)
Alanina/análogos & derivados , Amidas/síntesis química , Diabetes Mellitus Experimental/tratamiento farmacológico , Fructosa-Bifosfatasa/antagonistas & inhibidores , Hipoglucemiantes/síntesis química , Organofosfonatos/síntesis química , Profármacos/síntesis química , Tiazoles/síntesis química , Administración Oral , Alanina/síntesis química , Alanina/farmacocinética , Alanina/farmacología , Amidas/farmacocinética , Amidas/farmacología , Animales , Disponibilidad Biológica , Proteínas Sanguíneas/metabolismo , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Humanos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Masculino , Ratones , Organofosfonatos/farmacocinética , Organofosfonatos/farmacología , Profármacos/farmacocinética , Profármacos/farmacología , Unión Proteica , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Tiazoles/farmacocinética , Tiazoles/farmacologíaRESUMEN
Like most phosphonic acids, the recently discovered potent and selective thiazole phosphonic acid inhibitors of fructose 1,6-bisphosphatase (FBPase) exhibited low oral bioavailability (OBAV) and therefore required a prodrug to achieve oral efficacy. Syntheses of known phosphonate prodrugs did not afford the desired OBAV; hence, a new class of prodrugs was sought. Phosphonic diamides derived from amino acid esters were discovered as viable prodrugs, which met our preset goals: excellent aqueous stability over a wide pH range, benign byproducts (amino acids and low molecular weight alcohols), and most importantly good OBAV leading to robust oral glucose lowering effects. These desirable properties of phosphonic diamides represent significant improvements over existing prodrug classes. Optimization of the diamide prodrugs of phosphonic acid 2a (MB05032) led to the identification of diamide 8 (MB06322), the first reported orally efficacious FBPase inhibitor.