Discovery of novel and orally active NR2B-selective N-methyl-D-aspartate (NMDA) antagonists, pyridinol derivatives with reduced HERG binding affinity.

Abstract Novel NR2B antagonists with an amide tether were found by an approach to avoid pharmacophoric similarity to dofetilide. Structure–activity relationship investigation led to N -[ cis -4-hydroxy-4-(5-hydroxypyridin-2-yl)cyclohexyl]-3-henylpropanamide 14e as an orally active NR2B-subtype selective N -methyl- d -aspartate (NMDA) receptor antagonist with very weak HERG ( human ether-a-go-go related gene) binding (IC 50  > 30 μM). This compound exhibited potent in vivo anti-allodynic activity in the mouse partial sciatic nerve ligation (PSL) model (minimum effective dose = 10 mg/kg, po).