RESUMO
The 3,4-fused sulfamides, sulfonamides and sulfone have been identified as highly potent gamma-secretase inhibitors. Evaluation of the SAR of substitution within these series has allowed the identification of a range of compounds which significantly reduce brain A beta in transgenic mouse models and thus have potential as possible treatments for Alzheimer's disease.
Assuntos
Endopeptidases/metabolismo , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Sulfonas/química , Sulfonas/farmacologia , Secretases da Proteína Precursora do Amiloide , Animais , Ácido Aspártico Endopeptidases , Cristalografia por Raios X , Ciclização , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteases/química , Ratos , Relação Estrutura-Atividade , Sulfonas/síntese químicaRESUMO
The subtle modification of a selection of Abeta42 inhibiting non-steroidal anti-inflammatory drugs (NSAIDs), through synthesis of the geminal dimethyl analogues, was anticipated to ablate their cyclooxygenase activity whilst maintaining Abeta42 inhibition. Methylflurbiprofen 6 exhibited similar in vitro Abeta42 inhibition to its parent NSAID Flurbiprofen and was further evaluated in the Tg2576 mouse model of Alzheimer's disease and an animal model of gastro-intestinal (GI) impairment, but proved unviable for further clinical development.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Anti-Inflamatórios não Esteroides/síntese química , Encéfalo/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase/síntese química , Flurbiprofeno/síntese química , Fragmentos de Peptídeos/antagonistas & inibidores , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Encéfalo/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Inibidores de Ciclo-Oxigenase/uso terapêutico , Modelos Animais de Doenças , Flurbiprofeno/análogos & derivados , Flurbiprofeno/farmacologia , Flurbiprofeno/uso terapêutico , CamundongosRESUMO
A new series of gamma-secretase inhibitors was developed from an in-house screening hit based on a benzobicyclo[4.2.1]nonane core. Lead optimisation studies led to the development of a series of potent inhibitors and in vivo efficacy was demonstrated.