RESUMO
The synthesis and identification of sulfonamido-aryl ethers as potent bradykinin B1 receptor antagonists from a approximately 60,000 member encoded combinatorial library are reported. Two distinct series of compounds exhibiting different structure-activity relationships were identified in a bradykinin B1 whole-cell receptor-binding assay. Specific examples exhibit K(i) values of approximately 10nM.
Assuntos
Antagonistas de Receptor B1 da Bradicinina , Éteres/síntese química , Sulfonamidas/síntese química , Animais , Linhagem Celular , Técnicas de Química Combinatória , Humanos , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade , Sulfonamidas/farmacologiaRESUMO
The protease gamma-secretase plays a pivotal role in the synthesis of pathogenic amyloid-beta in Alzheimer's disease (AD). Here, we report a further extension to a series of cyclohexyl sulfone-based gamma-secretase inhibitors which has allowed the preparation of highly potent compounds which also demonstrate robust Abeta(40) lowering in vivo (e.g., compound 32, MED 1mg/kg p.o. in APP-YAC mice).
