Discovery of NR2B-selective antagonists via scaffold hopping and pharmacokinetic profile optimization

Abstract Selective N -methyl- d -aspartate receptor subunit 2B (NR2B) antagonists show potential as analgesic drugs, and do not cause side effects associated with non-selective N -methyl- d -aspartate (NMDA) antagonists. Using a scaffold-hopping approach, we previously identified isoxazole derivative 4 as a potent selective NR2B antagonist. In this study, further scaffold hopping of isoxazole derivative 4 and optimization of its pharmacokinetic profile led to the discovery of the orally bioavailable compound 6v . In a rat study of analgesia, 6v demonstrated analgesic effects against neuropathic pain.