RESUMEN
Pyrido[3,2-b]pyrazin-3(4H)-ones and pteridin-7(8H)-ones were evaluated as corticotropin-releasing factor-1 receptor antagonists. The synthesis, SAR studies and pharmacokinetic evaluation of these analogs are described herein.
Asunto(s)
Pteridinas/química , Pirazinas/química , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Animales , Ansiolíticos/síntesis química , Ansiolíticos/química , Ansiolíticos/farmacocinética , Semivida , Pteridinas/síntesis química , Pteridinas/farmacocinética , Pirazinas/síntesis química , Pirazinas/farmacocinética , Ratas , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Relación Estructura-ActividadRESUMEN
We report on the design of benzodiazepinones as peptidomimetics at the carboxy terminus of hydroxyamides. Structure-activity relationships of diazepinones were investigated and orally active gamma-secretase inhibitors were synthesized. Active metabolites contributing to Abeta reduction were identified by analysis of plasma samples from Tg2576 mice. In particular, (S)-2-((S)-2-(3,5-difluorophenyl)-2-hydroxyacetamido)-N-((S,Z)-3-methyl-4-oxo-4,5-dihydro-3H-benzo[d][1,2]diazepin-5-yl)propanamide (BMS-433796) was identified with an acceptable pharmacodynamic and pharmacokinetic profile. Chronic dosing of BMS-433796 in Tg2576 mice suggested a narrow therapeutic window and Notch-mediated toxicity at higher doses.
Asunto(s)
Alanina/análogos & derivados , Enfermedad de Alzheimer/enzimología , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Benzodiazepinonas/farmacología , Inhibidores Enzimáticos/farmacología , Alanina/farmacología , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides , Animales , Ratones , Ratones Transgénicos , Modelos MolecularesRESUMEN
2,3-Benzodiazepin-1,4-diones were designed as peptidomimetics at the carboxy terminus of hydroxyamides. Inhibition of brain Abeta production was improved by one of the compounds containing constrained modification.
Asunto(s)
Encéfalo/efectos de los fármacos , Endopeptidasas/metabolismo , Inhibidores de Proteasas/farmacología , Enfermedad de Alzheimer/enzimología , Amidas/química , Secretasas de la Proteína Precursora del Amiloide , Animales , Ácido Aspártico Endopeptidasas , Benzodiazepinas/síntesis química , Benzodiazepinas/farmacología , Encéfalo/metabolismo , Línea Celular , Diseño de Fármacos , Concentración 50 Inhibidora , Cetonas/síntesis química , Cetonas/farmacología , Ratones , Conformación Molecular , Imitación Molecular , Inhibidores de Proteasas/síntesis química , Unión ProteicaRESUMEN
Using a cell-based assay, we have identified optimal residues and key recognition elements necessary for inhibition of gamma-secretase. An (S)-hydroxy group or 3,5-difluorophenylacetyl group at the amino terminus and N-methyltertiary amide moiety at the carboxy terminus provided potent gamma-secretase inhibitors with an IC(50) <10 nM.
