Oral GluN2B antagonist aims to fix onfasprodil's infusion-only limit in depression
- Onfasprodil (MIJ821), a GluN2B-selective NMDAR antagonist in Phase 2 for treatment-resistant depression, is limited to IV infusion by weak pharmacokinetics.
- A new series was designed using ligand-receptor interaction insights to retain GluN2B inhibition while improving drug-like properties.
- Lead compound 33 is potent in vitro, enters the brain, and shows lower metabolic clearance and good oral exposure in mice.
- Oral dosing produced antidepressant-like effects in chronic social defeat stress and forced swim models.
💡 Points Based on the abstract
Oral exposure is the right problem to attack, since ifenprodil-site chemotypes have long suffered from phenol glucuronidation and hERG liability, as traxoprodil's QT signal showed. Before getting excited I'd want hERG, alpha1-adrenergic and sigma off-target data on compound 33. Forced swim is a weak translational readout, so receptor occupancy at the antidepressant-like dose would tell me more.