RESUMEN
SCH 58261 is a reported adenosine A(2A) receptor antagonist, which is active in rat in vivo models of Parkinson's Disease upon ip administration. However, it has poor selectivity versus the A(1) receptor and does not demonstrate oral activity. We report the design and synthesis of biaryl and heteroaryl analogs of SCH 58261 which improve the A(2A) receptor binding selectivity as well as the pharmacokinetic properties of SCH 58261. In particular, the quinoline 25 has excellent A(2A) receptor in vitro binding affinity and selectivity, sustained rat plasma levels upon oral dosing, and is active orally in a rat behavioral assay.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Química Farmacéutica/métodos , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Pirimidinas/síntesis química , Pirimidinas/farmacología , Triazoles/síntesis química , Triazoles/farmacología , Administración Oral , Animales , Conducta Animal/efectos de los fármacos , Diseño de Fármacos , Humanos , Modelos Químicos , Piperazinas/química , Quinolinas/química , Ratas , Relación Estructura-ActividadRESUMEN
Antagonism of the adenosine A2A receptor offers great promise in the treatment of Parkinson's disease. Employing the known pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine A2A antagonist SCH 58261 as a starting point, we identified the potent and selective (vs. A1) antagonist 11h, orally active in the rat haloperidol-induced catalepsy model. We further optimized this lead to the methoxyethoxyethyl ether 12a (SCH 420814), which shows broad selectivity, good pharmacokinetic properties, and excellent in vivo activity.