Abstract
The preclinical pharmacodynamic and pharmacokinetic properties of 4-methylbenzyl (3S, 4R)-3-fluoro-4-[(Pyrimidin-2-ylamino) methyl] piperidine-1-carboxylate (CERC-301), an orally bioavailable selective N-methyl-D-aspartate (NMDA) receptor subunit 2B (GluN2B) antagonist, were characterized to develop a translational approach based on receptor occupancy (RO) to guide CERC-301 dose selection in clinical trials of major depressive disorder. CERC-301 demonstrated high-binding affinity (Ki, 8.1 nmol L-1) specific to GluN2B with an IC50 of 3.6 nmol L-1 and no off-target activity. CERC-301 efficacy was demonstrated in the forced swim test with an efficacy dose (ED50) of 0.3-0.7 mg kg-1 (RO, 30-50%); increase in locomotor activity was observed at ED50 of 2 mg kg-1, corresponding to an RO of 75%. The predicted 50% RO concentration (Occ50) in humans was 400 nmol L-1, similar to that predicted for rat, dog, and monkey (300, 200, and 400 nmol L-1, respectively). Safety pharmacology and neurotoxicity studies raised no specific safety concerns. A first-in-human study in healthy males demonstrated a dose-proportional pharmacokinetic profile, with Tmax of ~1 h and t1/2 of 12-17 h. Based on the preclinical and pharmacodynamic data, doses of ≥8 mg in humans are hypothesized to have an acceptable safety profile and result in clinically relevant peak plasma exposure.
Original language | English (US) |
---|---|
Pages (from-to) | 1-12 |
Number of pages | 12 |
Journal | Pharmacology Research and Perspectives |
Volume | 3 |
Issue number | 6 |
DOIs | |
State | Published - Dec 1 2015 |
Keywords
- Depression
- GluN2B
- Major depressive disorder
- NMDA antagonist
ASJC Scopus subject areas
- Neurology
- Pharmacology, Toxicology and Pharmaceutics(all)