RESUMEN
Adducts from the intermolecular radical addition of N-xanthylacetyl-N-methanesulfanilides to Boc-protected allylamine undergo ring closure with loss of a methanesulfonyl radical to give benzazepin-2-ones. Upon deprotection and exposure to triethylamine, these compounds rearrange into 5-aryl-2-piperidones. This approach also represents a useful route to benzazepin-2-ones unsubstituted on the nitrogen atom of the azepinone ring.
Asunto(s)
Alilamina/química , Benzazepinas/síntesis química , Piperidonas/síntesis química , Benzazepinas/química , Catálisis , Ciclización , Estructura Molecular , Nitrógeno/química , Piperidonas/químicaRESUMEN
Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer's disease. We have recently disclosed a series of transition-state mimetic BACE-1 inhibitors showing nanomolar potency in cell-based assays. Amongst them, GSK188909 (compound 2) had favorable pharmacokinetics and was the first orally bioavailable inhibitor reported to demonstrate brain amyloid lowering in an animal model. In this Letter, we describe the reasons that led us to favor a second generation of inhibitors for further in vivo studies.
Asunto(s)
Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Inhibidores de Proteasas/química , Tiazinas/química , Administración Oral , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismo , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Sitios de Unión , Simulación por Computador , Etilaminas/síntesis química , Etilaminas/química , Etilaminas/farmacología , Humanos , Ratones , Inhibidores de Proteasas/farmacocinética , Ratas , Relación Estructura-Actividad , Tiazinas/síntesis química , Tiazinas/farmacocinéticaRESUMEN
Our first generation of hydroxyethylamine transition-state mimetic BACE-1 inhibitors allowed us to validate BACE-1 as a key target for Alzheimer's disease by demonstrating amyloid lowering in an animal model, albeit at rather high doses. Finding a molecule from this series which was active at lower oral doses proved elusive and demonstrated the need to find a novel series of inhibitors with improved pharmacokinetics. This Letter describes the discovery of such inhibitors.
Asunto(s)
Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Etilaminas/química , Inhibidores de Proteasas/química , Administración Oral , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismo , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Etilaminas/síntesis química , Etilaminas/farmacología , Humanos , Ratones , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Ratas , Relación Estructura-Actividad , Tiazinas/química , Tiazinas/farmacologíaRESUMEN
Our first generation of hydroxyethylamine BACE-1 inhibitors proved unlikely to provide molecules that would lower amyloid in an animal model at low oral doses. This observation led us to the discovery of a second generation of inhibitors having nanomolar activity in a cell-based assay and with the potential for improved pharmacokinetic profiles. In this Letter, we describe our successful strategy for the optimization of oral bioavailability and also give insights into the design of compounds with the potential for improved brain penetration.
Asunto(s)
Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Etilaminas/química , Inhibidores de Proteasas/química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Disponibilidad Biológica , Perros , Etilaminas/síntesis química , Etilaminas/farmacocinética , Ratones , Ratones Noqueados , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
2-Fluoropyridyl derivatives of allylic alcohols react with xanthates in the presence of lauroyl peroxide to give alkenes, often with high stereoselectivity. If the allylic alcohols are themselves derived from aldehydes or ketones, the overall process becomes a synthetic equivalent of the classical Wittig and related olefination reactions.
RESUMEN
BACE-1 inhibition has the potential to provide a disease-modifying therapy for the treatment of Alzheimer's disease. Optimization of a first generation of BACE-1 inhibitors led to the discovery of novel hydroxyethylamines (HEAs) bearing a tricyclic nonprime side. These derivatives have nanomolar cell potency and are orally bioavailable.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Benzotiadiazinas/síntesis química , Óxidos S-Cíclicos/síntesis química , Etilaminas/síntesis química , Administración Oral , Animales , Benzotiadiazinas/farmacocinética , Benzotiadiazinas/farmacología , Disponibilidad Biológica , Óxidos S-Cíclicos/farmacocinética , Óxidos S-Cíclicos/farmacología , Perros , Etilaminas/farmacocinética , Etilaminas/farmacología , Modelos Moleculares , Ratas , Relación Estructura-ActividadRESUMEN
This article is focusing on further optimization of previously described hydroxy ethylamine (HEA) BACE-1 inhibitors obtained from a focused library with the support of X-ray crystallography. Optimization of the non-prime side of our inhibitors and introduction of a 6-membered sultam substituent binding to Asn-294 as well as a fluorine in the C-2 position led to derivatives with nanomolar potency in cell-based assays.