RESUMEN
The synthesis and SAR of tolylamines with 5-HT(6) receptor antagonist activity is presented. The amine, core aromatic, peripheral aromatic, and ether linker moieties of HTS hit 1 were modulated and the effect on potency at 5-HT(6) examined. Tolylpiperidine ether 9h was found to possess desirable pharmacokinetic (PK) properties, and was also shown to enhance cognition in the rat novel object recognition paradigm.
Asunto(s)
Aminas/química , Receptores de Serotonina/química , Agonistas de Receptores de Serotonina/síntesis química , Animales , Química Orgánica/métodos , Química Farmacéutica/métodos , Diseño de Fármacos , Éteres/química , Concentración 50 Inhibidora , Cinética , Modelos Químicos , Ratas , Agonistas de Receptores de Serotonina/química , Agonistas de Receptores de Serotonina/farmacología , Relación Estructura-ActividadRESUMEN
The inhibition of the cytosolic isoenzyme BCAT that is expressed specifically in neuronal tissue is likely to be useful for the treatment of neurodegenerative and other neurological disorders where glutamatergic mechanisms are implicated. Compound 2 exhibited an IC50 of 0.8 microM in the hBCATc assays; it is an active and selective inhibitor. Inhibitor 2 also blocked calcium influx into neuronal cells following inhibition of glutamate uptake, and demonstrated neuroprotective efficacy in vivo. SAR, pharmacology, and the crystal structure of hBCATc with inhibitor 2 are described.
