RESUMO
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.
Assuntos
Pteridinas/química , Pirazinas/química , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Animais , Ansiolíticos/síntese química , Ansiolíticos/química , Ansiolíticos/farmacocinética , Meia-Vida , Pteridinas/síntese química , Pteridinas/farmacocinética , Pirazinas/síntese química , Pirazinas/farmacocinética , Ratos , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Relação Estrutura-AtividadeRESUMO
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
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.
