RESUMEN
The identification and subsequent optimisation of a selective non-peptidic NPY Y2 antagonist series is described. This led to the development of amine 2, a selective, soluble NPY Y2 receptor antagonist with enhanced CNS exposure.
Asunto(s)
Pirimidinas/química , Receptores de Neuropéptido Y/antagonistas & inhibidores , Compuestos de Espiro/química , Amidas/síntesis química , Amidas/química , Amidas/farmacocinética , Aminas/síntesis química , Aminas/química , Aminas/farmacocinética , Animales , Sistema Nervioso Central/efectos de los fármacos , Humanos , Microsomas Hepáticos/metabolismo , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Ratas , Receptores de Neuropéptido Y/metabolismo , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacocinética , Relación Estructura-ActividadRESUMEN
The identification of a highly selective D(2) partial agonist, D(3) antagonist tool molecule which demonstrates high levels of brain exposure and selectivity against an extensive range of dopamine, serotonin, adrenergic, histamine, and muscarinic receptors is described.
Asunto(s)
Encéfalo/efectos de los fármacos , Agonistas de Dopamina/farmacología , Antagonistas de Dopamina/farmacología , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D3/antagonistas & inhibidores , Animales , Encéfalo/metabolismoRESUMEN
A novel small molecule NPY Y2 antagonist (3) identified from high throughput screening is described. A subsequent SAR study and optimisation programme based around this molecule is also described, leading to the identification of potent and soluble pyridyl analogue 36.