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

R. Garner,Shobha Gopalakrishnan,J. Mccauley,R. Bednar,S. L. Gaul,S. Mosser,L. Kiss,J. Lynch,Shil Patel,Christine M. Fandozzi,A. Lagrutta,R. Briscoe,N. Liverton,B. Paterson,J. Vornov,R. Mazhari

Published 2015 in Pharmacology Research & Perspectives

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.

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