RESUMEN
A series of (N-benzyl-N-phenylsulfonamido)alkyl amides were developed from classic and parallel synthesis strategies. Compounds with good in vitro and in vivo γ-secretase activity were identified and described.
Asunto(s)
Amidas/química , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Inhibidores de Proteasas/química , Sulfonamidas/química , Amidas/síntesis química , Amidas/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Fragmentos de Péptidos/metabolismo , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/metabolismo , Unión Proteica , Relación Estructura-ActividadRESUMEN
The synthesis and gamma-secretase inhibition data for a series of carbamate-appended N-alkylsulfonamides are described. Carbamate 54 was found to significantly reduce brain Abeta in transgenic mice. 54 was also found to possess markedly improved brain levels in transgenic mice compared to previously disclosed 1 and 2.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Carbamatos/química , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Sulfonamidas/química , Sulfonamidas/farmacología , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Ratones , Ratones Transgénicos , Relación Estructura-ActividadRESUMEN
The synthesis and gamma-secretase inhibition data for a series of nitrogen-appended N-alkylsulfonamides (11-47) are described. Inhibition of brain Abeta in transgenic mice was demonstrated by two of these compounds (23 and 44).
Asunto(s)
Aminas/química , Aminas/farmacología , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Sulfonamidas/química , Sulfonamidas/farmacología , Alquilación , Aminas/síntesis química , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Animales , Azoles/síntesis química , Azoles/química , Azoles/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/enzimología , Encéfalo/metabolismo , Interacciones Hidrofóbicas e Hidrofílicas , Concentración 50 Inhibidora , Ratones , Ratones Transgénicos , Fragmentos de Péptidos/metabolismo , Inhibidores de Proteasas/síntesis química , Relación Estructura-Actividad , Sulfonamidas/síntesis químicaRESUMEN
A series of amino-caprolactam sulfonamides were developed from a screening hit. Compounds with good in vitro and in vivo gamma-secretase activity are reported.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Caprolactama/farmacología , Inhibidores Enzimáticos/farmacología , Caprolactama/química , Inhibidores Enzimáticos/químicaRESUMEN
A series of N-alkylbenzenesulfonamides were developed from a high throughput screening hit. Classic and parallel synthesis strategies were employed to produce compounds with good in vitro and in vivo gamma-secretase activity.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Sulfonamidas/química , Sulfonamidas/farmacología , Péptidos beta-Amiloides/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Ratones , Ratones Transgénicos , Estructura Molecular , Unión ProteicaRESUMEN
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.