RESUMO
The design, synthesis and SAR of a series of heterocyclic ring-constrained norepinephrine reuptake inhibitors are described. As racemates, the best compounds compare favorably with atomoxetine (IC(50)'s<10 nM) in potency at the transporter.
Assuntos
Proteínas da Membrana Plasmática de Transporte de Norepinefrina/química , Cloridrato de Atomoxetina , Química Farmacêutica/métodos , Inibidores do Citocromo P-450 CYP2D6 , Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A , Desenho de Fármacos , Humanos , Indenos/farmacologia , Concentração Inibidora 50 , Microssomos Hepáticos/enzimologia , Modelos Químicos , Norepinefrina/química , Norepinefrina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Propilaminas/química , Serotonina/química , Relação Estrutura-AtividadeRESUMO
The synthesis and SAR of a series of chiral heterocyclic ring-constrained norepinephrine reuptake inhibitors are described. The best compounds compare favorably with atomoxetine in potency (IC(50)s<10 nM), selectivity against the other monoamine transporters, and inhibition of CYP2D6 (IC(50)s>1 microM). In addition, the compounds are generally more stable than atomoxetine to oxidative metabolism and thus are likely to have lower clearance in humans.
Assuntos
Inibidores da Captação Adrenérgica/síntese química , Inibidores da Captação Adrenérgica/farmacologia , Química Farmacêutica/métodos , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/síntese química , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/farmacologia , Norepinefrina/química , Oxigênio/química , Inibidores da Captação Adrenérgica/química , Cloridrato de Atomoxetina , Citocromo P-450 CYP2D6/química , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Modelos Químicos , Conformação Molecular , Norepinefrina/metabolismo , Propilaminas/química , Propilaminas/farmacologia , Relação Estrutura-Atividade , Simportadores/químicaRESUMO
We report the characterization and optimization of drug-like small molecule inhibitors of tissue-nonspecific alkaline phosphatase (TNAP), an enzyme critical for the regulation of extracellular matrix calcification during bone formation and growth. High-throughput screening (HTS) of a small molecule library led to the identification of arylsulfonamides as potent and selective inhibitors of TNAP. Critical structural requirements for activity were determined, and the compounds were subsequently profiled for in vitro activity and bioavailability parameters including metabolic stability and permeability. The plasma levels following subcutaneous administration of a member of the lead series in rat was determined, demonstrating the potential of these TNAP inhibitors as systemically active therapeutic agents to target various diseases involving soft tissue calcification. A representative member of the series was also characterized in mechanistic and kinetic studies.