Preclinical pharmacology and pharmacokinetics of CERC‐301, a GluN2B‐selective N‐methyl‐D‐aspartate receptor antagonist

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 (K (i), 8.1 nmol L(−1)) specific to GluN2B with an IC (50) 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 (ED (50)) of 0.3–0.7 mg kg(−1) (RO, 30–50%); increase in locomotor activity was observed at ED (50) of 2 mg kg(−1), corresponding to an RO of 75%. The predicted 50% RO concentration (Occ(50)) 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 T (max) of ~1 h and t (1/2) 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.