RESUMEN
We report the design and synthesis of novel pyrrolo[3,2-b]quinoline containing heteroarene ethers as PDE10A inhibitors with good to excellent potency, selectivity and metabolic stability. Further optimization of this primary series resulted in the identification of 1-methyl-3-(4-{[3-(pyridine-4-yl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrolo[3,2-b]pyridine 13a with good hPDE10A potency (IC50: 6.3 nM), excellent selectivity over other related PDEs and desirable physicochemical properties. The compound exhibited high peripheral and adequate brain levels upon oral dosing in rodents. The compound also showed excellent efficacy in multiple preclinical animal models related to psychiatric disorders, particularly schizophrenia.
Asunto(s)
Diseño de Fármacos , Éteres/farmacología , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , Pirazinas/farmacología , Piridinas/farmacología , Animales , Perros , Relación Dosis-Respuesta a Droga , Éteres/administración & dosificación , Éteres/química , Haplorrinos , Humanos , Masculino , Ratones , Estructura Molecular , Inhibidores de Fosfodiesterasa/administración & dosificación , Inhibidores de Fosfodiesterasa/química , Pirazinas/administración & dosificación , Pirazinas/química , Piridinas/administración & dosificación , Piridinas/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
The synthesis and structure-activity relationship studies of a series of compounds from imidazopyridazinone scaffold as PDE7 inhibitors are disclosed. Potent analogs such as compounds 7 (31nM), 8 (27nM), and 9 (12nM) were identified. The PDE selectivity and pharmacokinetic profile of compounds 7, 8 and 9 are also disclosed. The adequate CNS penetration of compound 7 in mice allowed it to be tested in the MPTP induced PD model and haloperidol induced catalepsy model to probe the differential pharmacology of PDE7 in the striatal pathway.
