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
Heterocyclic replacement of the isophthalamide phenyl ring in hydroxyethylamine (HEA) BACE-1 inhibitors was explored. A variety of indole-1,3-dicarboxamide HEAs exhibited potent BACE-1 enzyme inhibition, but displayed poor cellular activity. Improvements in cellular activity and aspartic protease selectivity were observed for 7-azaindole-1,3-dicarboxamide HEAs. A methylprolinol-bearing derivative (10n) demonstrated robust reductions in rat plasma Aß levels, but did not lower rat brain Aß due to poor central exposure. The same analog exhibited a high efflux ratio in a bidirectional Caco-2 assay and was likely a substrate of the efflux transporter P-glycoprotein. X-ray crystal structures are reported for two indole HEAs in complex with BACE-1.
Assuntos
Aminas/química , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Indóis/síntese química , Inibidores de Proteases/química , Piridinas/síntese química , Aminas/síntese química , Aminas/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/sangue , Animais , Ácido Aspártico Endopeptidases/metabolismo , Sítios de Ligação , Cristalografia por Raios X , Indóis/química , Indóis/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Estrutura Terciária de Proteína , Piridinas/química , Piridinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
The present studies have identified a series of aminotriazines as novel 5-HT(7) receptor antagonists. Compounds 10 and 17 have high affinity for the 5-HT(7) receptor and do not bind to either the 5-HT(2C) or 5-HT(6) receptors. These compounds produce no agonist effects by themselves, and shift the dose-response curve of 5-CT to the right in the manner of an antagonist.