RESUMEN
The evaluation of a series of aminoisoindoles as ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors and the discovery of a clinical candidate drug for Alzheimer's disease, (S)-32 (AZD3839), are described. The improvement in permeability properties by the introduction of fluorine adjacent to the amidine moiety, resulting in in vivo brain reduction of Aß40, is discussed. Due to the basic nature of these compounds, they displayed affinity for the human ether-a-go-go related gene (hERG) ion channel. Different ways to reduce hERG inhibition and increase hERG margins for this series are described, culminating in (S)-16 and (R)-41 showing large in vitro margins with BACE1 cell IC(50) values of 8.6 and 0.16 nM, respectively, and hERG IC(50) values of 16 and 2.8 µM, respectively. Several compounds were advanced into pharmacodynamic studies and demonstrated significant reduction of ß-amyloid peptides in mouse brain following oral dosing.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Indoles/síntesis química , Pirimidinas/síntesis química , Administración Oral , Alquinos/síntesis química , Alquinos/farmacocinética , Alquinos/farmacología , Amidas/síntesis química , Amidas/farmacocinética , Amidas/farmacología , Secretasas de la Proteína Precursora del Amiloide/química , Péptidos beta-Amiloides/metabolismo , Animales , Ácido Aspártico Endopeptidasas/química , Disponibilidad Biológica , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Línea Celular , Cristalografía por Rayos X , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Femenino , Transferencia Resonante de Energía de Fluorescencia , Humanos , Enlace de Hidrógeno , Indoles/farmacocinética , Indoles/farmacología , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Estructura Molecular , Fragmentos de Péptidos/metabolismo , Permeabilidad , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The evaluation of a series of bicyclic aminoimidazoles as potent BACE-1 inhibitors is described. The crystal structures of compounds 14 and 23 in complex with BACE-1 reveal hydrogen bond interactions with the protein important for achieving potent inhibition. The optimization of permeability and efflux properties of the compounds is discussed as well as the importance of these properties for attaining in vivo brain efficacy. Compound (R)-25 was selected for evaluation in vivo in wild type mice and 1.5h after oral co-administration of 300µmol/kg (R)-25 and efflux inhibitor GF120918 the brain Aß40 level was reduced by 17% and the plasma Aß40 level by 76%.