RESUMO
We report herein the discovery of novel integrase-LEDGF/p75 allosteric inhibitors (INLAIs) based on a benzene scaffold 3. This scaffold can extend substituents from the C1 position unlike the common pyridine scaffolds 2. Structure-activity relationship studies showed that the sulfonamide linker at the C1 position was important for the antiviral activity. Interaction between sulfonamide and Q95 was observed by X-ray crystallography. Compound 31h showed more potent antiviral activity (EC50 (NL432) = 3.9 nM) than BI-224436 (EC50 (NL432) = 56 nM), suggesting the potential of the newly designed scaffold 3.
Assuntos
Regulação Alostérica/efeitos dos fármacos , Antivirais/farmacologia , Derivados de Benzeno/química , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Animais , Antivirais/química , Antivirais/metabolismo , Derivados de Benzeno/metabolismo , Derivados de Benzeno/farmacologia , Sítios de Ligação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/química , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Ratos , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
Genetic evidence points to deposition of amyloid-ß (Aß) as a causal factor for Alzheimer's disease. Aß generation is initiated when ß-secretase (BACE1) cleaves the amyloid precursor protein. Starting with an oxazine lead 1, we describe the discovery of a thiazine-based BACE1 inhibitor 5 with robust Aß reduction in vivo at low concentrations, leading to a low projected human dose of 14 mg/day where 5 achieved sustained Aß reduction of 80% at trough level.