RESUMEN
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.
Asunto(s)
Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/química , Clorhidrato de Atomoxetina , Química Farmacéutica/métodos , Inhibidores del Citocromo P-450 CYP2D6 , Citocromo P-450 CYP3A , Inhibidores del Citocromo P-450 CYP3A , Diseño de Fármacos , Humanos , Indenos/farmacología , Concentración 50 Inhibidora , Microsomas Hepáticos/enzimología , Modelos Químicos , Norepinefrina/química , Norepinefrina/metabolismo , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/metabolismo , Propilaminas/química , Serotonina/química , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Inhibidores de Captación Adrenérgica/síntesis química , Inhibidores de Captación Adrenérgica/farmacología , Química Farmacéutica/métodos , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/síntesis química , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/farmacología , Norepinefrina/química , Oxígeno/química , Inhibidores de Captación Adrenérgica/química , Clorhidrato de Atomoxetina , Citocromo P-450 CYP2D6/química , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Conformación Molecular , Norepinefrina/metabolismo , Propilaminas/química , Propilaminas/farmacología , Relación Estructura-Actividad , Simportadores/químicaRESUMEN
The design synthesis and SAR of a series of chiral ring-constrained norepinephrine reuptake inhibitors with improved physicochemical properties is described. Typical compounds are potent (IC(50)s<10 nM), selective against the other monoamine transporters, weak CYP2D6 inhibitors (IC(50)s>1 microM) and stable to oxidation by human liver microsomes. In addition, the compounds exhibit a favorable polarity profile.