RESUMO
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.
Assuntos
Amidas/química , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Inibidores de Proteases/química , Sulfonamidas/química , Amidas/síntese química , Amidas/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Fragmentos de Peptídeos/metabolismo , Inibidores de Proteases/síntese química , Inibidores de Proteases/metabolismo , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Carbamatos/química , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Camundongos , Camundongos Transgênicos , Relação Estrutura-AtividadeRESUMO
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).
Assuntos
Aminas/química , Aminas/farmacologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Alquilação , Aminas/síntese química , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Azóis/síntese química , Azóis/química , Azóis/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Encéfalo/metabolismo , Interações Hidrofóbicas e Hidrofílicas , Concentração Inibidora 50 , Camundongos , Camundongos Transgênicos , Fragmentos de Peptídeos/metabolismo , Inibidores de Proteases/síntese química , Relação Estrutura-Atividade , Sulfonamidas/síntese químicaRESUMO
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.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Sulfonamidas/química , Sulfonamidas/farmacologia , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Camundongos , Camundongos Transgênicos , Estrutura Molecular , Ligação ProteicaRESUMO
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.
Assuntos
Alanina/análogos & derivados , Doença de Alzheimer/enzimologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Benzodiazepinonas/farmacologia , Inibidores Enzimáticos/farmacologia , Alanina/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides , Animais , Camundongos , Camundongos Transgênicos , Modelos MolecularesRESUMO
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.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Caprolactama/farmacologia , Inibidores Enzimáticos/farmacologia , Caprolactama/química , Inibidores Enzimáticos/químicaRESUMO
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.
Assuntos
Encéfalo/efeitos dos fármacos , Endopeptidases/metabolismo , Inibidores de Proteases/farmacologia , Doença de Alzheimer/enzimologia , Amidas/química , Secretases da Proteína Precursora do Amiloide , Animais , Ácido Aspártico Endopeptidases , Benzodiazepinas/síntese química , Benzodiazepinas/farmacologia , Encéfalo/metabolismo , Linhagem Celular , Desenho de Fármacos , Concentração Inibidora 50 , Cetonas/síntese química , Cetonas/farmacologia , Camundongos , Conformação Molecular , Mimetismo Molecular , Inibidores de Proteases/síntese química , Ligação ProteicaRESUMO
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.