RESUMEN
Highly potent and brain-penetrant phosphodiesterase 10A (PDE10A) inhibitors based on the 2-oxindole scaffold were designed and synthesized. (2-Oxo-1,3-oxazolidin-3-yl)phenyl derivative 1 showed the high P-glycoprotein (P-gp) efflux (efflux ratio (ER)=6.2) despite the potent PDE10A inhibitory activity (IC50=0.94 nM). We performed an optimization study to improve both the P-gp efflux ratio and PDE10A inhibitory activity by utilizing structure-based drug design (SBDD) techniques based on the X-ray crystal structure with PDE10A. Finally, 1-(cyclopropylmethyl)-4-fluoro-5-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (19e) was identified with improved P-gp efflux (ER=1.4) and an excellent PDE10A inhibitory activity (IC50=0.080 nM). Compound 19e also exhibited satisfactory brain penetration, and suppressed PCP-induced hyperlocomotion with a minimum effective dose of 0.3mg/kg by oral administration in mice.
Asunto(s)
Encéfalo/metabolismo , Diseño de Fármacos , Indoles/química , Indoles/síntesis química , Indoles/farmacología , Hidrolasas Diéster Fosfóricas/química , Piridazinas/síntesis química , Piridazinas/farmacología , Administración Oral , Animales , Sitios de Unión , Dominio Catalítico , Cristalografía por Rayos X , Activación Enzimática/efectos de los fármacos , Semivida , Indoles/farmacocinética , Ratones , Conformación Molecular , Simulación del Acoplamiento Molecular , Actividad Motora/efectos de los fármacos , Oxindoles , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/química , Inhibidores de Fosfodiesterasa/farmacocinética , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , Piridazinas/química , Piridazinas/farmacocinéticaRESUMEN
A new combination system, the oxidation of sulfides using aqueous NaOCl in the presence of a catalytic amount of imide under two-phase conditions, has been developed. The combination effectively converts various sulfides to the corresponding sulfoxides and sulfones. It was deduced that the imide could react with NaOCl to produce N-chloroimide, which would play roles of both the active oxidizing reagent and phase transfer catalyst.